Spiro-Sulfonamide Derivatives As Inhibitors Of Myeloid Cell Leukemia-1 (MCL-1) Protein

ABSTRACT

The disclosure is directed to compounds of Formula IPharmaceutical compositions comprising compounds of Formula I as well as methods of their use and preparation, are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 62/758,202, filed on Nov. 9, 2018; U.S. ProvisionalApplication No. 62/907,451, filed on Sep. 27, 2019; and U.S. ProvisionalApplication No. 62/909,635, filed on Oct. 2, 2019. Each of theseapplications is incorporated by reference in its entirety herein.

TECHNICAL FIELD

The disclosure is directed to MCL-1 inhibitors and methods of their use.

BACKGROUND

Apoptosis (programmed cell death) is a highly conserved cellular processthat is required for embryonic development and normal tissue homeostasis(Ashkenazi A. et al, Nat. Rev. Drug Discov. 2017, 16, 273-284).Apoptotic-type cell death involves morphological changes such ascondensation of the nucleus, DNA fragmentation as well as biochemicalphenomena such as the activation of caspases which cause damage to keystructural components of the cell, resulting in its disassembly anddeath. Regulation of the process of apoptosis is complex and involvesthe activation or repression of several intracellular signaling pathways(Cory S. et al, Nature Review Cancer 2002, 2, 647-656; Thomas L. W. etal, FEBS Lett. 2010, 584, 2981-2989; Adams J. M. et al., Oncogene 2007,26, 1324-1337)

The Bcl-2 protein family, which includes both pro-apoptotic andanti-apoptotic members, plays a pivotal role in the regulation of theapoptosis process (Youle R. J. et al, Nat. Rev. Mol. Cell Biol. 2008, 9,47-59; Kelly G. L. et al, Adv. Cancer Res. 2011, 111, 39-96). Bcl-2,Bcl-XL, Bcl-W, Mcl-1 and A1 are anti-apoptotic proteins and they share acommon BH regions. In contrast, the pro-apoptotic family members aredivided into two groups. The multi-region pro-apoptotic proteins, suchas Bax, Bak and Bok, are conventionally thought to have BH1-3 regions,whereas the BH3-only proteins are proposed to share homology in the BH3region only. Members of BH3-only proteins include Bad, Bim, Bid, Noxa,Puma, Bik/Blk, Bmf, Hrk/DP5, Beclin-1 and Mule (Xu G. et al, Bioorg.Med. Chem. 2017, 25, 5548-5556; Hardwick J. M. et al, Cell. 2009, 138,404; Reed J. C., Cell Death Differ. 2018, 25, 3-6; Kang M. H. et al,Clin Cancer Res 2009, 15, 1126-1132). The pro-apoptotic members (such asBAX and BAK), upon activation, form a homo-oligomer in the outermitochondrial membrane that leads to pore formation and the escape ofmitochondrial contents, a step into triggering apoptosis. Antiapoptoticmembers of the Bcl-2 family (such as Bcl-2, Bel-XL, and Mcl-1) block theactivity of BAX and BAK. In normal cells, this process is tightlyregulated. Abnormal cells can dysregulate this process to avoid celldeath. One of the ways that cancer cells can accomplish this is byupregulating the antiapoptotic members of the Bcl-2 family of proteins.Overexpression or up-regulation of the anti-apoptotic Bcl-2 familyproteins enhance cancer cell survival and cause resistance to a varietyof anticancer therapies.

Aberrant expression or function of the proteins responsible forapoptotic signaling contributes to numerous human pathologies includingauto-immune diseases, neurodegeneration (such as Parkinson's disease,Alzheimer's disease and ischaemia), inflammatory diseases, viralinfections and cancer (such as colon cancer, breast cancer, small-celllung cancer, non-small-cell lung cancer, bladder cancer, ovarian cancer,prostate cancer, chronic lymphoid leukemia, lymphoma, myeloma, acutemyeloid leukemia, pancreatic cancer, etc.) (Hanahan D. et al, Cell 2000,100. 57-70). Herein, it is prospective to target key apoptosisregulators for cancer treatment (Kale J. et al, Cell Death Differ. 2018,25, 65-80; Vogler M. et al, Cell Death Differ. 2009, 16, 360-367).

By overexpressing one or more of these pro-survival proteins, cancercells can evade elimination by normal physiological processes and thusgain a survival advantage. Myeloid Cell Leukemia-1 (Mcl-1) is a memberof the pro-survival Bcl-2 family of proteins. Mcl-1 has the distincttrait of being essential for embryonic development as well as thesurvival of all hematopoietic lineages and progenitor populations. Mcl-1is one of the most common genetic aberrations in human cancer and ishighly expressed in many tumor types. Mcl-1 overexpression in humancancers is associated with high tumor grade and poor survival (BeroukhimR. et al, Nature 2010, 463, 899-905). Mcl-1 overexpression preventscancer cells from undergoing programmed cell death (apoptosis), allowingthe cells to survive despite widespread genetic damage. Further, itsamplification is associated with both intrinsic and acquired resistanceto a wide variety of antitumorigenic agents including chemotherapeuticagents such as microtubule binding agents, paclitaxel and gemcitabine,as well as apoptosis-inducing agents such as TRAIL, the Bcl-2 inhibitor,venetoclax, and the Bcl-2/Bcl-XL dual inhibitor navitoclax. Not only dogene silencing approaches that specifically target Mcl-1 circumvent thisresistance phenotype, but certain cancer cell types frequently undergocell death in response to Mcl-1 silencing, indicating a dependence onMcl-1 for survival. Consequently, approaches that inhibit Mcl-1 functionare of considerable interest for cancer therapy (Wertz I. E et al,Nature 2011, 777, 110-114; Zhang B. et al., Blood 2002, 99, 1885-1893).

SUMMARY

The disclosure is directed to compounds of Formula I:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   Z is CH or N;    -   Q is —O—, —S—, —S(O)—, or —S(O)₂—;    -   the moiety -W¹-W²-W³ is —CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—,        —O—CR^(2B)R^(2C)—CR²R^(2A)—, —CR²R^(2A)—CR^(2B)R^(2C)—O—,        —NR^(2B)—CR^(2B)R^(2C)—CR²R^(2A)—,        —CR²R^(2A)—CR^(2B)R^(2C)—NR^(2B)—, —S—CR^(2B)R^(2C)—CR²R^(2A),        or —CR²R^(2A)—CR^(2B)R^(2C)—S—;    -   L¹ is absent or is optionally substituted —C₁-C₆alkylene-;    -   L² is absent or is optionally substituted cycloalkylene,        optionally substituted heterocycloalkylene, optionally        substituted arylene, or optionally substituted heteroarylene;    -   L³ is absent, or is —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—, —C(═O)O—,        —NR^(6A)C(O)—, —C(═O)NR^(6A)—, —OC(═O)N(R^(6A))—,        —NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—,        or —NR^(6A)S(O)₂—;    -   L⁴ is absent, or is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is        absent, —CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—,        —NR⁶—, —OC(═O)—, —C(═O)O—, —NR^(6A)C(O)—, —C(═O)NR^(6A)—,        —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—,        —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or        —NR^(6A)S(O)₂—; or is        —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—;    -   L⁵ is absent, or is —C₁-C₆ alkylene-, —C₂-C₆ alkenylene-, —C₂-C₆        alkynylene-, -arylene-, -heteroarylene-, -cycloalkenylene-,        -cycloalkylene-, -heterocycloalkylene-, wherein said C₁-C₆        alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, arylene,        heteroarylene, cycloalkenylene, cycloalkylene, or        heterocycloalkylene groups are optionally substituted;    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—, —(CR⁷R⁸)_(s)O(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t)—, —(CR⁷R⁸)_(s)S(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t)—, —(CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)NR^(9A)C(O)(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)OC(O)NR^(9A)(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)SNR^(9A)C(O)O(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)SNR^(9A)S(O)(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)NR^(9A)S(O)₂(CR⁷R⁸)_(t)—;        —(CR⁷R⁸)_(s)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—; —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—,        or —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—;    -   each n is independently 0-3;    -   each m is independently 0-2;    -   each p is independently 0-4;    -   each q is independently 0-4;    -   each s is independently 0-3;    -   each t is independently 0-4;    -   each R is independently -D, -halo, —CN, —NO₂, —C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₁-C₆alkoxy, -cycloalkyl, —OR^(a), —SR^(a),        —C(O)R^(b), —C(O)OR^(a), —NR^(c)R^(d), —C(O)NR^(c)R^(d), or        —S(O)₂R^(a); wherein said —C₁-C₆alkyl, —C₂-C₆alkenyl,        —C₁-C₆alkoxy, or -cycloalkyl is optionally substituted;    -   each R¹ is independently -D, -halo, —CN, —NO₂, —C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OR^(a), —SR^(a), —NR^(c)R^(d),        —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(a), —C(O)NR^(c)R^(d),        —S(O)₂R^(a); -aryl, -heteroaryl, -cycloalkyl, or        -heterocycloalkyl, wherein said —C₁-C₆alkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, -cycloalkyl, -heterocycloalkyl, -aryl, or        -heteroaryl is optionally substituted;    -   each R², R^(2A), or R^(2a) is independently H, D, halo, OR^(a),        optionally substituted C₁-C₆alkyl, or R² and R^(2A) that are        attached to the same carbon atom may, together with the carbon        atom to which they are both attached, form an optionally        substituted cycloalkyl ring;    -   each R^(2B) and R^(2C) is independently H, D, optionally        substituted C₁-C₆alkyl, or R^(2B) and R^(2C) may, together with        the carbon atom to which they are both attached, form an        optionally substituted cycloalkyl ring;    -   R³ is H, D, —C₁-C₆alkyl, —C₃-C₆alkenyl, —C₃-C₆alkynyl,        cycloalkyl, heterocycloalkyl, C(O)R^(b), C(O)OR^(a), or        C(O)NR^(c)R^(d); wherein said C₁-C₆alkyl, —C₃-C₆alkenyl,        —C₃-C₆alkynyl, cycloalkyl, or heterocycloalkyl is optionally        substituted; or R³ is —C₁-C₆alkyl substituted at the C₁ carbon        atom with —OR^(3A) wherein R^(3A) is C₁-C₆alkyl, —PO₃H,        —C(O)OR^(2C), or —C(O)NR^(3A)R^(3B) wherein R^(3A) and R^(3B)        are each independently H, D, optionally substituted C₁-C₆alkyl;    -   each R⁴ or R⁷ is independently H, D, halo, —OH, —CN, —NO₂,        —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl, —OR^(a), —SR^(a), —NR^(c)R^(d),        —NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(a), —C(O)OR^(a),        —C(O)NR^(c)R^(d), —S(O)R^(b), or —S(O)₂R^(b), wherein said        C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkenyl, or        heterocycloalkyl is optionally substituted;    -   each R^(4A) or R^(4B) is independently H, D, -Me, —CF₃ or —F;    -   each R⁵ or R⁸ is independently H, D, fluoro, —C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C(O)R^(b), —C(O)OR^(a),        —C(O)NR^(c)R^(d), aryl, heteroaryl, cycloalkyl, cycloalkenyl,        heterocycloalkyl, or heterocycloalkenyl, wherein said        C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl is optionally substituted;    -   or R⁴ and R⁵ together with the C atom to which they are attached        form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl ring, each optionally substituted;    -   or an R⁴ and an R⁵ attached to adjacent carbon atoms, together        with the C atoms to which they are attached, form a cycloalkyl,        cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each        optionally substituted;    -   or R⁷ and R⁸ together with the C atom to which they are both        attached form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl ring, each optionally substituted, each        optionally substituted;    -   or an R⁷ and an R⁸ attached to adjacent carbon atoms, together        with the C atoms to which they are attached, form a cycloalkyl,        cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each        optionally substituted;    -   each R⁶ or R⁹ is independently H, D, —C₁-C₆alkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, —OC₁-C₆alkyl, —C(O)R^(b), —C(O)OR^(a),        —C(O)NR^(c)R^(d), —S(O)R^(b) or —S(O)₂R^(b), aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl group, wherein said C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OC₁-C₆alkyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl ring, is optionally substituted;    -   or R⁹ together with an R⁷ or an R⁸ forms an optionally        substituted heterocyclic alkylene;    -   each R^(6A), R^(6B), R^(9A), or R^(9B) is independently H, D,        —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, cycloalkyl,        cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein        said C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, cycloalkyl,        cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is        optionally substituted;    -   or R^(6A) and R^(6B) together with the N atoms to which they are        attached form an optionally substituted heterocycloalkyl or        heterocycloalkenyl ring;    -   or R^(9A) and R^(9B) together with the N atoms to which they are        attached form an optionally substituted heterocycloalkyl or        heterocycloalkenyl ring; each R^(a) is independently H, D,        —C(O)R^(b), —C(O)OR^(c), —C(O)NR^(c)R^(d), —P(OR^(c))₂,        —P(O)R^(c)R^(b), —P(O)OR^(c)OR^(b), —S(O)R^(b),        —S(O)NR^(c)R^(d), —S(O)₂R^(b), —S(O)₂NR^(c)R^(d),        —B(OR^(c))(OR^(b)), SiR^(b) ₃, —C₁-C₁₀alkyl, —C₂-C₁₀ alkenyl,        —C₂-C₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,        heterocycloalkyl, or heterocycloalkenyl wherein said C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, cycloalkyl,        cycloalkenyl, heteroaryl, heterocycloalkyl, or        heterocycloalkenyl is optionally substituted;    -   each R^(b), is independently H, D, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,        heterocycloalkyl, or heterocycloalkenyl wherein said —C₁-C₆        alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, aryl, cycloalkyl,        cycloalkeneyl, heteroaryl, heterocycloalkyl, or        heterocycloalkenyl is optionally substituted;    -   each R^(c) or R^(d) is independently H, D, —C₁-C₁₀ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl, wherein said C₁-C₁₀ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl are each optionally substituted;    -   or R^(c) and R^(d), together with the N atom to which they are        both attached, form an optionally substituted monocyclic or        multicyclic heterocycloalkyl, or optionally substituted        monocyclic or multicyclic heterocycloalkenyl group.

Stereoisomers of the compounds of Formula I and the pharmaceutical saltsand solvates thereof, are also contemplated, described, and encompassedherein. Methods of using compounds of Formula I are described, as wellas pharmaceutical compositions including the compounds of Formula I.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an ORTEP representation of the compound of Example 34.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The disclosure may be more fully appreciated by reference to thefollowing description, including the following definitions and examples.Certain features of the disclosed compositions and methods which aredescribed herein in the context of separate aspects, may also beprovided in combination in a single aspect. Alternatively, variousfeatures of the disclosed compositions and methods that are, forbrevity, described in the context of a single aspect, may also beprovided separately or in any subcombination.

The term “alkyl,” when used alone or as part of a substituent group,refers to a straight- or branched-chain hydrocarbon group having from 1to 12 carbon atoms (“C₁-C₁₂”), preferably 1 to 6 carbons atoms(“C₁-C₆”), in the group. Examples of alkyl groups include methyl (Me,C₁alkyl), ethyl (Et, C₂alkyl), n-propyl (C₃alkyl), isopropyl (C₃alkyl),butyl (C₄alkyl), isobutyl (C₄alkyl), sec-butyl (C₄alkyl), tert-butyl(C₄alkyl), pentyl (C₅alkyl), isopentyl (C₅alkyl), tert-pentyl (C₅alkyl),hexyl (C₆alkyl), isohexyl (C₆alkyl), and the like.

The term “haloalkyl,” when used alone or as part of a substituent group,refers to a straight- or branched-chain hydrocarbon group having from 1to 12 carbon atoms (“C₁-C₁₂”), preferably 1 to 6 carbons atoms(“C₁-C₆”), in the group, wherein one or more of the hydrogen atoms inthe group have been replaced by a halogen atom. Examples of haloalkylgroups include trifluoromethyl (—CF₃, C₁haloalkyl), trifluoroethyl(—CH₂CF₃, C₂haloalkyl), and the like.

The term “alkylene” when used alone or as part of a substituent group,refers to an alkyl diradical, i.e., a straight- or branched-chainhydrocarbon group having from 1 to 12 carbon atoms (“C₁-C₁₂”),preferably 1 to 6 carbons atoms (“C₁-C₆”), in the group, wherein thegroup is directly attached to two other variable groups.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups thusalso encompass cycloalkenyl groups. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2 fused rings) groups, spirocycles, andbridged rings (e.g., a bridged bicycloalkyl group). Ring-forming carbonatoms of a cycloalkyl group can be optionally substituted by oxo orsulfido (e.g., C(O) or C(S)). Also included in the definition ofcycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo or thienyl derivatives of cyclopentane, cyclohexane, andthe like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,or 10 ring-forming carbons (C₃₋₁₀). In some embodiments, the cycloalkylis a C₃₋₁₀ monocyclic or bicyclic cyclocalkyl. In some embodiments, thecycloalkyl is a C₃₋₁₀ monocyclic or bicyclic cycloalkyl which isoptionally substituted by CH₂F, CHF₂, CF₃, and CF₂CF₃. In someembodiments, the cycloalkyl is a C₃₋₇ monocyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₄₋₁₀ spirocycle or bridged cycloalkyl.Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In some embodiments, cycloalkyl arecyclic-containing, non-aromatic hydrocarbon groups having from 3 to 12carbon atoms (“C₃-C₁₂”), preferably from 3 to 6 carbon atoms (“C₃-C₆”).Examples of cycloalkyl groups include, for example, cyclopropyl (C₃;3-membered), cyclobutyl (C₄; 4-membered), cyclopropylmethyl (C₄),cyclopentyl (C₅), cyclohexyl (C₆), 1-methylcyclopropyl (C₄),2-methylcyclopentyl (C₄), adamantanyl (C₁₀), and the like.

The term “cycloalkylene” when used alone or as part of a substituentgroup refers to a cycloalkyl diradical, i.e., a cyclic-containing,non-aromatic hydrocarbon group having from 3 to 14 carbon atoms(“C₃-C₁₄”; or 3-14 membered), for example 3 to 12 carbon atoms(“C₃-C₁₂”), preferably from preferably from 3 to 7 carbon atoms(“C₃-C₇”, or 3-7 membered) or 3 to 6 carbon atoms (“C₃-C₆”), wherein thegroup is directly attached to two other variable groups. Cycloalkylenegroups include spirocycloalkylene groups.

The term “cycloalkenylene” refers to a cycloalkenylene diradical.

The term “spirocycloalkyl” when used alone or as part of a substituentgroup refers to a non-aromatic hydrocarbon group containing twocycloalkyl rings, and wherein the two cycloalyl rings share a singlecarbon atom in common.

The term “spirocycloalkylene” when used alone or as part of asubstituent group refers to a spirocycloalkyl diradical, i.e., anon-aromatic hydrocarbon group containing two cycloalkyl rings, andwherein the two cycloalyl rings share a single carbon atom in common,and wherein the group is directly attached to two other variable groups.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S and B, and wherein the ring-forming carbon atomsand heteroatoms of the heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), orS(0)2, etc.). Heterocycloalkyl groups include monocyclic and polycyclic(e.g., having 2 fused rings) systems. Included in heterocycloalkyl aremonocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 memberedheterocycloalkyl groups. Heterocycloalkyl groups can also includespirocycles and bridged rings (e.g., a 5-10 membered bridgedbiheterocycloalkyl ring having one or more of the ring-forming carbonatoms replaced by a heteroatom independently selected from N, O, S andB). The heterocycloalkyl group can be attached through a ring-formingcarbon atom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In some embodiments, the heterocycloalkyl group contains3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments,the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1to 2 heteroatoms or 1 heteroatom. In some embodiments, theheterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1or 2 heteroatoms independently selected from N, O, S and B and havingone or more oxidized ring members. Example heterocycloalkyl groupsinclude pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl,tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene,1,2,3,4-tetrahydroisoquinoline, azabicyclo[3.1.O]hexanyl,diazabicyclo[3.1.O]hexanyl, oxabicyclo[2.1.l]hexanyl,azabicyclo[2.2.l]heptanyl, diazabicyclo[2.2.1]heptanyl,azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.l]heptanyl,azabicyclo[3.2.l]octanyl, diazabicyclo[3.2.1]octanyl,oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl,diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl,diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl,azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl,azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl,diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl,diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl and the like.

In some embodiments, heterocycloalkyl refers to any three to tenmembered monocyclic or bicyclic, saturated ring structure containing atleast one heteroatom selected from the group consisting of O, N and S.The heterocycloalkyl group may be attached at any heteroatom or carbonatom of the ring such that the result is a stable structure. Examples ofsuitable heterocycloalkyl groups include, but are not limited to,azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl,quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, andthe like.

The term “heterocycloalkylene” when used alone or as part of asubstituent group refers to a heterocycloalkyl diradical. In someembodiments heterocycloalkylene any three to ten membered monocyclic orbicyclic, saturated ring structure containing at least one heteroatomselected from the group consisting of O, N and S, wherein the ringstructure is directly attached to two other variable groups.

In some embodiments, the term “spiroheterocycloalkyl” when used alone oras part of a substituent group refers to a non-aromatic group containingtwo rings, at least one of which is a heterocycloalkyl ring, and whereinthe two rings share a single carbon atom in common.

In some embodiments, the term “spirocycloalkylene” when used alone or aspart of a substituent group refers to a spirocycloalkyl diradical. Insome embodiments, spirocycloalkylene is a non-aromatic group containingtwo rings, at least one of which is a heterocycloalkyl ring, and whereinthe two rings share a single carbon atom in common, and wherein thegroup is directly attached to two other variable groups.

The term “alkenyl” when used alone or as part of a substituent grouprefers to a straight- or branched-chain group having from 2 to 12 carbonatoms (“C₂-C₁₂”), preferably 2 to 4 carbons atoms (“C₂-C₄”), in thegroup, wherein the group includes at least one carbon-carbon doublebond. Examples of alkenyl groups include vinyl (—CH═CH₂; C₂alkenyl),allyl (—CH₂—CH═CH₂; C₃alkenyl), propenyl (—CH═CHCH₃; C₃alkenyl);isopropenyl (—C(CH₃)═CH₂; C₃alkenyl), butenyl (—CH═CHCH₂CH₃; C₄alkenyl),sec-butenyl (—C(CH₃)═CHCH₃; C₄alkenyl), iso-butenyl (—CH═C(CH₃)₂;C₄alkenyl), 2-butenyl (—CH₂CH═CHCH₃; C₄alkyl), pentenyl (CH═CHCH₂CH₂CH₃or CH2═CHCH₂CH₂CH₂—; C₅alkenyl), and the like.

The term “alkenylene” when used alone or as part of a substituent grouprefers to a alkenyl diradical, i.e., a straight- or branched-chain grouphaving from 2 to 12 carbon atoms (“C₂-C₁₂”), preferably 2 to 4 carbonsatoms (“C₂-C₄”), in the group, wherein the group includes at least onecarbon-carbon double bond, and wherein the group is directly attached totwo other variable groups.

The term “alkynyl” when used alone or as part of a substituent grouprefers to a straight- or branched-chain group having from 2 to 12 carbonatoms (“C₂-C₁₂”), preferably 2 to 4 carbons atoms (“C₂-C₄”), in thegroup, wherein the group includes at least one carbon-carbon triplebond. Examples of alkynyl groups include ethynyl (—C≡CH; C₂alkynyl),propragyl (—CH₂—CH═CH; C₃alkynyl), and the like.

The term “alkynylene” when used alone or as part of a substituent grouprefers to an alkynyl diradical, i.e., a straight- or branched-chaingroup having from 2 to 12 carbon atoms (“C₂-C₁₂”), preferably 2 to 4carbons atoms (“C₂-C₄”), in the group, wherein the group includes atleast one carbon-carbon triple bond, and wherein the group is directlyattached to two other variable groups.

The term “aryl” when used alone or as part of a substituent group refersto a monocyclic all carbon aromatic ring or a multicyclic all carbonring system wherein the rings are aromatic. Thus, aryl also includesmultiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4aryl rings) having about 9 to 14 carbon atoms. In some embodiments,“aryl” refers to a mono- or bicyclic-aromatic hydrocarbon ring structurehaving 6 or 10 carbon atoms in the ring, wherein one or more of thecarbon atoms in the ring is optionally substituted. Exemplarysubstituents include halogen atoms, —C₁-C₃ alkyl groups, andC₁-C₃haloalkyl groups. Halogen atoms include chlorine, fluorine,bromine, and iodine. C₁-C₃haloalkyl groups include, for example, —CF₃,—CH₂CF₃, and the like.

The term “arylene” when used alone or as part of a substituent grouprefers to an aryl diradical. In some embodiments, “arylene” refers to amono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10carbon atoms in the ring, wherein one or more of the carbon atoms in thering is optionally substituted, and wherein the ring structure isdirectly attached to two other variable groups.

The term “heteroaryl” when used alone or as part of a substituent group,the term “heteroaryl” as used herein refers to a monocyclic aromaticring that has at least one atom other than carbon in the ring, whereinthe atom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multicyclic ring systems that have atleast one such aromatic ring. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. “Heteroaryl” also includes multiplecondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings)wherein a heteroaryl group is condensed with one or more rings selectedfrom heteroaryls or aryls. Thus, a heteroaryl (a single aromatic ring ormultiple condensed ring system) has about 1-20 carbon atoms and about1-6 heteroatoms within the heteroaryl ring system. A heteroaryl (amonocyclic aromatic ring or multicyclic condensed ring system) can alsohave about 5 to 12 or about 5 to 10 members within the heteroaryl ring.The rings of a multicyclic ring system can be connected to each othervia fused, spiro and bridged bonds when allowed by valency requirements.In some embodiments, “heteroaryl” refers to a mono- or bicyclic-aromaticring structure including carbon atoms as well as up to four heteroatomsselected from nitrogen, oxygen, and sulfur. In such embodiments,heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms. Theheteroaryl moiety can be optionally substituted. Exemplary substituentsinclude halogen atoms; —C₁-C₃ alkyl groups, and C₁-C₃haloalkyl groups.Halogen atoms include chlorine, fluorine, bromine, and iodine.

The term “heteroarylene” when used alone or as part of a substituentgroup refers to a heteroaryl diradical. In some embodiments,heteroarylene is a mono- or bicyclic-aromatic ring structure includingcarbon atoms as well as up to four heteroatoms selected from nitrogen,oxygen, and sulfur, wherein the ring structure is directly attached totwo other variable groups.

The term “halo” refers to a halogen substituent (i.e., —F, —Cl, —Br, or—I).

The term “oxo” refers to an oxygen substituent that is connected by adouble bond (i.e., ═O).

The term “alkoxy” when used alone or as part of a substituent grouprefers to an oxygen radical attached to an alkyl group by a single bond.Examples of alkoxy groups include methoxy (—OCH₃), ethoxy (—OCH₂CH₃),isopropoxy (—OCH(CH₃)₂) and the like.

The term “haloalkoxy” when used alone or as part of a substituent grouprefers to an oxygen radical attached to a haloalkyl group by a singlebond. Examples of haloalkoxy groups include —OCF₃, —OCH₂CF₃, —OCH(CF₃)₂,and the like.

When a range of carbon atoms is used herein, for example, C₁-C₆, allranges, as well as individual numbers of carbon atoms are encompassed.For example, “C₁-C₃” includes C₁-C₃, C₁-C₂, C₂-C₃, C₁, C₂, and C₃.

The term “C₁-C₆alk” when used alone or as part of a substituent grouprefers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atomsand includes, for example, —CH₂—, —CH(CH₃)—, —CH(CH₃)—CH₂—, and—C(CH₃)₂—. The term “—C₀alk-” refers to a bond. In some aspects, theC₁-C₆alk can be substituted with one or more substituents.

In some embodiments wherein a group is described as “optionallysubstituted” (e.g., when a C₁-C₆alkyl, —C₁-C₆alkylene-, C₁-C₁₀ alkyl,—C₂-C₁₀alkenyl, —C₂-C₁₀alkynyl, —C₂-C₆ alkenylene-, —C₂-C₆ alkynylene-,cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene, aryl,arylene, heteroaryl, or heteroarylene group is optionally substituted),the optional substituent may be one or more of D, halo, oxo, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆alkyl-NR^(c1)R^(d1), —(CH₂CH₂O)_(o)C₁-C₆alkyl wherein o is 1-10; C₂₋₆alkenyl-NR^(c1)R^(d1), C₂₋₆ alkynyl-NR^(c1)R^(d1), OC₂₋₆alkyl-NR^(c1)R^(d1), CN, NO₂, N₃, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), —CH₂C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), —NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), C(═NR^(g1))NR^(c1)R^(d1),NR^(c1)C(═NR^(g1))NR^(c1)R^(d1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(b1), >SO(═NR^(b1));S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1);aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, spirocycloalkyl,spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl are optionallysubstituted with D, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ alkyl-NR^(c1)R^(d1), C₂₋₆alkenyl-NR^(c1)R^(d1), C₂₋₆ alkynyl-NR^(c1)R^(d1), OC₂₋₆alkyl-NR^(c1)R^(d1), CN, NO₂, N₃, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), —CH₂C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), —NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), C(═NR^(g1))NR^(c1)R^(d1),NR^(c1)C(═NR^(g1))NR^(c1)R^(d1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1).

In these optional substituents, each R^(a1) is independently H, D, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl, wherein said C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy.

In these optional substituents each R^(b1) is independently H, D,C₁-C₆alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl, wherein said C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy.

In these optional substituents R^(c1) or R^(d1) is independently H,C₁-C₁₀ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroaryl aryl, and biheteroaryl, whereinsaid C₁-C₁₀ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroaryl aryl, and biheteroaryl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,C(O)OR^(a1), C(O)R^(b1), S(O)₂R^(b1), alkoxyalkyl, and alkoxyalkoxy;

Alternatively, in some embodiments, these optional substituents R^(c2)and R^(d2) together with the N atom to which they are attached form a4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group,each optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,C(O)OR^(a1), C(O)R^(b1), S(O)₂R^(b1), alkoxyalkyl, and alkoxyalkoxy;

In these optional substituents R^(e1) is independently H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, (C₁-C₆ alkoxy)-C₁-C₆ alkyl, C₂-C₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl.

In these optional substituents R^(f1) is independently H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl.

In these optional substituents R^(g1) is independently H, CN, or NO₂.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, e.g., in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of thedisclosure that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxy ethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

A “solvate” refers to a physical association of a compound of Formula Iwith one or more solvent molecules.

“Subject” includes humans. The terms “human,” “patient,” and “subject”are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Compounds of the present disclosure,” and equivalent expressions, aremeant to embrace compounds of Formula I or Formula II as describedherein, as well as their respective subgenera, which expression includesthe stereoisomers (e.g., entaniomers, diastereomers) and constitutionalisomers (e.g., tautomers) of compounds of Formula I or Formula II aswell as the pharmaceutically acceptable salts, where the context sopermits.

As used herein, the term “isotopic variant” refers to a compound thatcontains proportions of isotopes at one or more of the atoms thatconstitute such compound that is greater than natural abundance. Forexample, an “isotopic variant” of a compound can be radiolabeled, thatis, contain one or more radioactive isotopes, or can be labeled withnon-radioactive isotopes such as for example, deuterium (²H or D),carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will be understoodthat, in a compound where such isotopic substitution is made, thefollowing atoms, where present, may vary, so that for example, anyhydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N,and that the presence and placement of such atoms may be determinedwithin the skill of the art.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers,” for example, diastereomers, enantiomers, andatropisomers. The compounds of this disclosure may possess one or moreasymmetric centers; such compounds can therefore be produced asindividual (R)- or (S)-stereoisomers at each asymmetric center, or asmixtures thereof. Unless indicated otherwise, the description or namingof a particular compound in the specification and claims is intended toinclude all stereoisomers and mixtures, racemic or otherwise, thereof.Where one chiral center exists in a structure, but no specificstereochemistry is shown for that center, both enantiomers, individuallyor as a mixture of enantiomers, are encompassed by that structure. Wheremore than one chiral center exists in a structure, but no specificstereochemistry is shown for the centers, all enantiomers anddiastereomers, individually or as a mixture, are encompassed by thatstructure. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art.

In some aspects, the disclosure is directed to a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof.

In some aspects, Z in Formula I is CH or N. In some embodiments, Z isCH. In other embodiments, Z is N.

In some aspects, Q in Formula I is —O—, —S—, —S(O)—, or —S(O)₂—. In someembodiments, Q is —O—. In some embodiments, Q is —S—. In someembodiments, Q is —S(O)—. In some embodiments, Q is —S(O)₂—.

In some aspects, the moiety -W¹-W²-W³ in Formula I is—CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—, —O—CR^(2B)R^(2C)—CR²R^(2A)—,—CR²R^(2A)—CR^(2B)R^(2C)—O—, —NR^(2B)—CR^(2B)R^(2C)—CR²R^(2A)—,—CR²R^(2A)—CR^(2B)R^(2C)— NR^(2B)—, —S—CR^(2B)R^(2C)—CR²R^(2A), or—CR²R^(2A)—CR^(2B)R^(2C)—S—.

In some embodiments, the moiety -W¹-W²-W³ in Formula I is—CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—. In some embodiments, the moiety-W¹-W²-W³ in Formula I is —O—CR^(2B)R^(2C)—CR²R^(2A)—. In someembodiments, the moiety -W¹-W²-W³ in Formula I—CR²R^(2A)—CR^(2B)R^(2C)—O—. In some embodiments, the moiety -W¹-W²-W³in Formula I is —NR^(2B)—CR^(2B)R^(2C)—CR²R^(2A)—. In some embodiments,the moiety -W¹-W²-W³ in Formula I —CR²R^(2A)—CR^(2B)R^(2C)— NR^(2B) Insome embodiments, the moiety -W¹-W²-W³ in Formula I is—S—CR^(2B)R^(2C)—CR²R^(2A). In some embodiments, the moiety -W¹-W²-W³ inFormula I is —CR²R^(2A)—CR^(2B)R^(2C)—S—.

In some aspects, L¹ in Formula I is absent, or is —C₁-C₆alkylene-, forexample, —C₁alkylene, —C₂alkylene, —C₃alkylene, —C₄alkylene,—C₅alkylene, or —C₆alkylene, wherein the C₁-C₆alkylene is optionallysubstituted. In some embodiments, L¹ in Formula I is —C₁-C₆alkylene-,for example, —C₁alkylene, —C₂alkylene, —C₃alkylene, —C₄alkylene,—C₅alkylene, or —C₆alkylene, wherein the C₁-C₆alkylene is optionallysubstituted. In some embodiments, L¹ in Formula I is optionallysubstituted —C₁alkylene. In some embodiments, L¹ in Formula I is —CH₂—.

In some aspects, L² in Formula I is optionally substitutedcycloalkylene, optionally substituted heterocycloalkylene, optionallysubstituted arylene, or optionally substituted heteroaryl ene.

In some embodiments, L² in Formula I is 3-7 membered cycloalkylene, 4-7membered heterocycloalkylene, arylene, or heteroarylene; each optionallysubstituted.

In some embodiments, L² is optionally substituted cycloalkylene oroptionally substituted heterocycloalkylene.

In some embodiments, L² is optionally substituted cyclobutylene oroptionally substituted pyrrolidinyl.

In some embodiments, L² in Formula I is 3-7 membered cycloalkylene, forexample, 3-membered cycloalkylene, 4-membered cycloalkylene, 5-memberedcycloalkylene, 6-membered cycloalkylene, or 7-membered cycloalkylene. Insome embodiments, L² is 4-membered cycloalkylene. In some embodiments,L² is cyclobutylenyl.

In some embodiments, L² in Formula I is 4-7 memberedheterocycloalkylene, for example, 4-membered heterocycloalkylene,5-membered heterocycloalkylene, 6-membered heterocycloalkylene, or7-membered heterocycloalkylene. In some embodiments, L² in Formula I is5-membered heterocycloalkylene. In some embodiments, L² is pyrrolidinyl.

In other embodiments, L² in Formula I is heteroarylene. In someembodiments, the heteroarylene is pyrazolyl.

In some aspects, L³ in Formula I is absent, or is —(CR⁴R⁵)_(p)—,—(CR⁴R⁵)_(p)O—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—,—C(═O)O—, —NR^(6A)C(O)—, —C(═O)NR^(6A)—, —OC(═O)N(R^(6A))—,—NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or—NR^(6A)S(O)₂—.

In some embodiments, L³ in Formula I is absent. In some embodiments, L³is —(CR⁴R⁵)_(p)—. In some embodiments, L³ is —(CR⁴R⁵)_(p)O—. In someembodiments, L³ is —O—. In some embodiments, L³ is —S—. In someembodiments, L³ is —S(O)—. In some embodiments, L³ is —S(O)₂—. In someembodiments, L³ is —C(═O)—. In some embodiments, L³ is —NR⁶—. In someembodiments, L³ is —OC(═O)—. In some embodiments, L³ is —C(═O)O—. Insome embodiments, L³ is —NR^(6A)C(O). In some embodiments, L³ is—C(═O)NR^(6A)—. In some embodiments, L³ is —OC(═O)N(R^(6A))—. In someembodiments, L³ is —NR^(6A)C(O)O—. In some embodiments, L³ is—S(═O)NR^(6A)—. In some embodiments, L³ is —NR^(6A)S(O)—. In someembodiments, L³ is —S(═O)₂NR^(6A)—. In some embodiments, L³ is—NR^(6A)S(O)₂—.

In some aspects, L⁴ in Formula I is absent, or is—(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is absent, —CR^(4A)═CR^(4B)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—, —C(═O)O—,—NR^(6A)C(O)—, —C(═O)NR^(6A)—, —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—,—NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or—NR^(6A)S(O)₂—; or is —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—.

In some embodiments, L⁴ in Formula I is absent. In other embodiments, L⁴in Formula I is —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula I is —(CR⁴R⁵)_(p)—O—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula I is —(CR⁴R⁵)_(p)—S—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula I is —(CR⁴R⁵)_(p)—S(O)—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula I is —(CR⁴R⁵)_(p)—S(O)₂—(CR⁴R⁵)_(q)—. Inother embodiments, L⁴ in Formula I is —(CR⁴R⁵)_(p)—C(═O)—(CR⁴R⁵)_(q)—.In other embodiments, L⁴ in Formula I is —(CR⁴R⁵)_(p)—NR⁶—(CR⁴R⁵)_(q)—.In other embodiments, L⁴ in Formula I is—(CR⁴R⁵)_(p)—OC(═O)—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ in Formula Iis —(CR⁴R⁵)_(p)—C(═O)O—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ in FormulaI is —(CR⁴R⁵)_(p)—NR^(6A)C(O)—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ inFormula I is —(CR⁴R⁵)_(p)—C(═O)NR^(6A)—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula I is—(CR⁴R⁵)_(p)—NR^(6A)C(O)R^(6B)—CR⁴R⁵)_(q)—. In other embodiments, L⁴ inFormula I is —(CR⁴R⁵)_(p)—OC(═O)N(R^(6A))—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula I is —(CR⁴R⁵)_(p)—NR^(6A)C(O)O—(CR⁴R⁵)_(q)—.In other embodiments, L⁴ in Formula I is—(CR⁴R⁵)_(p)—S(═O)NR^(6A)—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ inFormula I is —(CR⁴R⁵)_(p)—NR^(6A)S(O)—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula I is —(CR⁴R⁵)_(p)—S(═O)₂NR^(6A)—(CR⁴R⁵)_(q)—.In other embodiments, L⁴ in Formula I is—(CR⁴R⁵)_(p)—NR^(6A)S(O)₂—(CR⁴R⁵)_(q)—. In some embodiments, L⁴ is—(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—.

In some aspects, L⁵ in Formula I is absent, or is —C₁-C₆ alkylene-,—C₂-C₆ alkenylene-, —C₂-C₆ alkynylene-, -arylene-, -heteroarylene-,-cycloalkenylene-, -cycloalkylene-, -heterocycloalkylene-, wherein theC₁-C₆ alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, arylene, heteroarylene, cycloalkenylene, cycloalkylene, or heterocycloalkylene groups areoptionally substituted.

In some embodiments, L⁵ in Formula I is absent. In other embodiments, L⁵in Formula I is C₁-C₆ alkylene, for example, C₁alkylene, C₂alkylene,C₃alkylene, C₄alkylene, C₅alkylene, or C₆alkylene, each optionallysubstituted.

In other embodiments, L⁵ in Formula I is C₂-C₆ alkenylene, for example,C₂alkenylene, C₃alkenylene, C₄alkenylene, C₅alkenylene, or C₆alkenylene,each optionally substituted.

In other embodiments, L⁵ in Formula I is C₂-C₆ alkynylene, for example,C₂alkynylene, C₃alkynylene, C₄alkynylene, C₅alkynylene, or C₆alkynylene,each optionally substituted.

In other embodiments, L⁵ in Formula I is an optionally substitutedarylene. In some embodiments, L⁵ in Formula I is a 6- to 10-memberedarylene, for example phenylene or naphthylene. In some embodiments, L⁵in Formula I is a phenylene.

In other embodiments, L⁵ in Formula I is an optionally substitutedheteroarylene. In some embodiments, L⁵ in Formula I is a 5- to10-membered heteroarylene, for example, pyrazolyl, thiazolyl,imidazolyl, or pyridinyl. In some embodiments, L⁵ in Formula I ispyrazolyl. In other embodiments, L⁵ in Formula I is thiazolyl. In otherembodiments, L⁵ in Formula I is imidazolyl. In some embodiments, L⁵ inFormula I is pyridinyl.

In other embodiments, L⁵ in Formula I is an optionally substitutedcycloalkenylene. In some embodiments, L⁵ in Formula I is a 3- to12-membered cycloalkenylene, for example, cyclohexenyl.

In other embodiments, L⁵ in Formula I is an optionally substitutedcycloalkylene. In some embodiments, L⁵ in Formula I is a 3- to7-membered monocyclic cycloalkylene, for example, cyclopentanyl,cyclohexanyl, and the like. In some embodiments, L⁵ in Formula I iscyclopentanyl.

In other embodiments, L⁵ in Formula I is a 6- to 12-membered bicycliccycloalkylene.

In other embodiments, L⁵ in Formula I is an optionally substitutedheterocycloalkylene. In some embodiments, L⁵ in Formula I is anoptionally substituted 3- to 7-membered monocyclic heterocycloalkylenegroup, for example, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,piperazinyl, and the like. In some embodiments, L⁵ in Formula I ispyrrolidinyl. In some embodiments, L⁵ in Formula I is tetrahydrofuranyl.In some embodiments, L⁵ in Formula I is piperidinyl. In someembodiments, L⁵ in Formula I is piperazinyl.

In other embodiments, L⁵ in Formula I is an optionally substituted 6- to12-membered bicyclic heterocycloalkylene group.

In some embodiments, L⁵ is absent, or is —C₁-C₆ alkylene-, —C₂-C₆alkenylene-, —C₂-C₆ alkynylene-, a 6- to 10-membered arylene, 5- to10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to7-membered monocyclic cycloalkylene, or 6- to 12 bicyclic cycloalkylene,a 3- to 7-membered monocyclic heterocycloalkylene, or 6- to 12-memberedbicyclic heterocycloalkylene group.

In some aspects, L⁶ in Formula I is absent, or is (CR⁷R⁸)_(s),(CR⁷R⁸)_(s)O(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)S(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR^(9A)C(O)(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)OC(O)NR^(9A)(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR^(9A)C(O)O(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)NR^(9A)S(O)(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR^(9A)S(O)₂(CR⁷R⁸)_(t);—(CR⁷R⁸)_(s)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t);—(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—, or —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—.

In some embodiments, L⁶ in Formula I is absent. In other embodiments, L⁶in Formula I is (CR⁷R⁸)_(s). In other embodiments, L⁶ in Formula I is(CR⁷R⁸)_(s)O(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula I is(CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula I is(CR⁷R⁸)_(s)S(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula I is(CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula I is(CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula I is(CR⁷R⁸)_(s)NR^(9A)C(O)(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula Iis (CR⁷R⁸)_(s)OC(O)NR^(9A)(CR⁷R⁸)_(t). In other embodiments, L⁶ inFormula I is (CR⁷R⁸)_(s)NR^(9A)C(O)O(CR⁷R⁸)_(t). In other embodiments,L⁶ in Formula I is (CR⁷R⁸)_(s)NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t). In otherembodiments, L⁶ in Formula I is (CR⁷R⁸)_(s)NR^(9A)S(O)(CR⁷R⁸)_(t). Inother embodiments, L⁶ in Formula I is(CR⁷R⁸)_(s)NR^(9A)S(O)₂(CR⁷R⁸)_(t). In other embodiments, L⁶ in FormulaI is —(CR⁷R⁸)_(s)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t). In other embodiments, L⁶in Formula I is (CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t). In other embodiments, L⁶ inFormula I is —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—. In other embodiments, L⁶in Formula I is —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—.

In some embodiments, L⁶ is absent, or is —(CR⁷R⁸)_(s)—, —O(CR⁷R⁸)_(t)—,—NR⁹(CR⁷R⁸)_(t)—, —S(CR⁷R⁸)_(t)—, —S(O)(CR⁷R⁸)_(t)—, —S(O)₂(CR⁷R⁸)_(t)—,—NR^(9A)C(O)(CR⁷R⁸)_(t)—, —C(O)NR^(9A)(CR⁷R⁸)_(t)—,—R^(9A)C(O)O(CR⁷R⁸)_(t)—, —NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—,—NR^(9A)S(O)(CR⁷R⁸)_(t)—, —NR^(9A)S(O)₂(CR⁷R⁸)_(t)—;—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—, —C(═O)(CR⁷R⁸)_(t)—; —C(═O)(CR⁷R⁸)_(t)—O—,or —C(═O)(CR⁷R⁸)_(t)—NR⁶—.

In some aspects, in Formula I, each n is independently 0-3. In someembodiments, n=0. In other embodiments, n=1. In other embodiments, n=2.In other embodiments, n=3.

In some aspects, in Formula I, each m is independently 0-2. In someembodiments, m=0. In other embodiments, m=1. In other embodiments, m=2.

In some aspects, in Formula I, each p is independently 0-4. In someembodiments, p=0. In other embodiments, p=1. In other embodiments, p=2.In other embodiments, p=3. In other embodiments, p=4.

In some aspects, in Formula I, each q is independently 0-4. In someembodiments, q=0. In other embodiments, q=1. In other embodiments, q=2.In other embodiments, q=3. In yet other embodiments, q=4.

In some aspects, in Formula I, each s is independently 0-3. In someembodiments, s=0. In other embodiments, s=1. In other embodiments, s=2.In other embodiments, s=3.

In some aspects, in Formula I, each t is independently 0-4. In someembodiments, t=0. In other embodiments, t=1. In other embodiments, t=2.In other embodiments, t=3. In other embodiments, t=4.

In some aspects, each R in Formula I is independently -D, -halo, —CN,—NO₂, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₁-C₆alkoxy, -cycloalkyl, —OR^(a),—SR^(a), —C(O)R^(b), —C(O)OR^(a), —NR^(c)R^(d), —C(O)NR^(c)R^(d), or—S(O)₂R^(a); wherein said —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₁-C₆alkoxy, or-cycloalkyl is optionally substituted.

In some embodiments, R is halo, for example, Cl or F. In someembodiments, R is —SR^(a), for example —SCH₃. In other embodiments, R is—C₁-C₆alkyl, for example —CH₃.

In some aspects, each R¹ in Formula I is independently -D, -halo, —CN,—NO₂, —C₁-C₆alkyl, —C₁-C₆alkenyl, —C₁-C₆alkynyl, —OR^(a), —SR^(a),—NR^(c)R^(d), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(a), —C(O)NR^(c)R^(d),—S(O)₂R^(a); -aryl, -heteroaryl, -cycloalkyl, or -heterocycloalkyl,wherein the —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, -cycloalkyl,-heterocycloalkyl, -aryl, or -heteroaryl is optionally substituted.

In some embodiments, R¹ in Formula I is halo, for example, Cl or F. Inother embodiments, R¹ in Formula I is —C₁-C₆alkyl substituted withfluorine, for example —CF₃. In other embodiments, R¹ in Formula I is—C₁-C₆alkyl, for example, —C₆alkyl, —C₅alkyl, —C₄alkyl, —C₃alkyl,—C₂alkyl, —C₁alkyl. In some embodiments, R¹ in Formula I is —C₁ alkylsubstituted with —CN. In other embodiments, R¹ in Formula I iscycloalkyl, for example, cyclopropane, cyclobutane, cyclopentane, andthe like. In other embodiments, R¹ in Formula I is cyclopropanesubstituted with —CN.

In some aspects, each R², R^(2A), or R^(2a) is independently H, D, halo,OR^(a), optionally substituted C₁-C₆alkyl, or R² and R^(2A) that areattached to the same carbon atom may, together with the carbon atom towhich they are both attached, form an optionally substituted cycloalkylring.

In some embodiments, R², R^(2A), and R^(2a) in Formula I are each H.

In other embodiments, R², R^(2A), or R^(2a) in Formula I is C₁-C₆alkyl,for example —CH₃ or —CH₂CH₃.

In other embodiments, R² and R^(2A) that are attached to the same carbonatom, together with the carbon atom to which they are both attached,form an optionally substituted 3-6 membered cycloalkyl ring. In someembodiments, R² and R^(2A) that are attached to the same carbon atom,together with the carbon atom to which they are both attached, form acyclopropane ring.

In other aspects, R² and R^(2a) that are attached to the same carbonatom, together with the carbon atom to which they are both attached,form an optionally substituted 3-6 membered cycloalkyl ring. In someembodiments, R² and R^(2a) that are attached to the same carbon atom,together with the carbon atom to which they are both attached, form acyclopropane ring.

In some aspects, each R^(2B) and R^(2C) in Formula I is independently H,D, optionally substituted C₁-C₆alkyl, or R^(2B) and R^(2C) may, togetherwith the carbon atom to which they are both attached, form an optionallysubstituted cycloalkyl ring.

In some embodiments, R^(2B) and R^(2C) in Formula I are each H.

In other embodiments, R^(2B) and R^(2C) that are attached to the samecarbon atom together with the carbon atom to which they are bothattached, form a cyclopropane ring.

In some aspects, R³ in Formula I is H, D, —C₁-C₆alkyl, —C₃-C₆alkenyl,—C₃-C₆alkynyl, cycloalkyl, heterocycloalkyl, C(O)R^(b), C(O)OR^(a), orC(O)NR^(c)R^(d); wherein said C₁-C₆alkyl, —C₃-C₆alkenyl, —C₃-C₆alkynyl,cycloalkyl, or heterocycloalkyl is optionally substituted; or R³ is—C₁-C₆alkyl substituted at the C₁ carbon atom with —OR^(3A) whereinR^(3A) is C₁-C₆alkyl, —PO₃H, —C(O)OR^(2C), or —C(O)NR^(3A)R^(3B) whereinR^(3A) and R^(3B) are each independently H, D, optionally substitutedC₁-C₆alkyl.

In some embodiments, R³ in Formula I is H. In other embodiments, R³ inFormula I is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, C₁alkyl, —CH3, and the like.

In some aspects, each R⁴ or R⁷ in Formula I is independently H, D, halo,—OH, —CN, —NO₂, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl,heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, —OR^(a), —SR^(a), —NR^(c)R^(d), —NR^(a)R^(c),—C(O)R^(b), —OC(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(d), —S(O)R^(b), or—S(O)₂R^(b), wherein said C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionallysubstituted.

In some embodiments, R⁴ is Formula I is H. In some embodiments, R⁴ isFormula I is —OH. In other embodiments, R⁴ in Formula I is —C₁-C₆alkyl,for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, —CH₃,and the like. In other embodiments, R⁴ is Formula I is —OR^(a), forexample, —OCH₃.

In some embodiments, R⁷ in Formula I is H. In other embodiments, R⁷ inFormula I is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, C₁alkyl, —CH₃, and the like. In some embodiments, R⁷in Formula I is —CH₃. In other embodiments, R⁷ in Formula I is —OR^(a),for example, —OCH₃.

In some aspects, each R^(4A) or R^(4B) in Formula I is independently H,D, -Me, —CF₃ or —F. In some embodiments, R^(4A) is H. In someembodiments, R^(4B) is H.

In some aspects, each R⁵ or R⁸ in Formula I is independently H, D,fluoro, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C(O)R^(b),—C(O)OR^(a), —C(O)NR^(c)R^(d), aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein theC₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionallysubstituted.

In some embodiments, R⁵ in Formula I is H. In other embodiments, R⁵ inFormula I is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, C₁alkyl, —CH₃, and the like. In some embodiments, R⁵in Formula I is —CH₃.

In some embodiments, R⁸ in Formula I is H. In other embodiments, R⁸ inFormula I is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, C₁alkyl, —CH₃, and the like. In some embodiments, R⁸in Formula I is —CH₃.

In some embodiments each R⁷ and each R⁸ is independently, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl, oroptionally substituted —C₁-C₆alkyl.

In other embodiments, each R⁷ and each R⁸ is independently H, optionallysubstituted 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, oroptionally substituted —C₁-C₆alkyl.

In other embodiments, each R⁷ and each R⁸ is independently H, —CH₃,-cyclopropyl, —CH₂CH₃, or —CH(CH₃)₂.

In other embodiments, each R⁷ and each R⁸ is independently H, or a—C₁-C₆alkyl group optionally substituted with —OH, optionallysubstituted —OC₁-C₆alkyl, optionally substituted—(CH₂CH₂O)_(o)C₁-C₆alkyl wherein o is 1-10, or —C(O)NR^(c1)R^(d1)wherein R^(c1) and R^(d1) are independently H, optionally substituted—C₁-C₆alkyl, optionally substituted cycloalkyl, or optionallysubstituted heterocycloalkyl.

In other embodiments, each R⁷ and each R⁸ is independently H, or—C₁-C₆alkyl group is optionally substituted with —OH, —OC₁-C₆alkyl,—(CH₂CH₂O)_(o)C₁-C₆alkyl wherein o is 1-10, or —C(O)NR^(c1)R^(d1)wherein R^(c1) and R^(d1) are independently H, C₁-C₆alkyl, or 4-7membered heterocycloalkyl; or wherein or R^(c1) and R^(d1), togetherwith the N atom to which they are both attached, form a multicyclic 4-7membered heterocycloalkyl ring optionally substituted with halo,—OC₁-C₆alkyl, or —C₁-C₆alkyl optionally substituted with —OH or—OC₁-C₆alkyl.

In some aspects, R⁴ and R⁵ together with the C atom to which they areattached form a cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl ring, each optionally substituted.

In other aspects, R⁴ and an R⁵ attached to adjacent carbon atoms,together with the C atoms to which they are attached, form a cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, eachoptionally substituted.

In some embodiments, each R⁷ and each R⁸ is independently H, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl, oroptionally substituted —C₁-C₆alkyl; or R⁷ and R⁸ attached to the samecarbon atom, together with that carbon atom, form an optionallysubstituted cycloalkyl ring or an optionally substitutedheterocycloalkyl ring; or R⁷ and R⁸ attached to adjacent carbon atoms,together with those carbon atoms, form an optionally substitutedcycloalkyl ring or and optionally substituted heterocycloalkyl ring.

In some embodiments, each R⁷ and each R⁸ is independently H, optionallysubstituted 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, oroptionally substituted —C₁-C₆alkyl; or wherein R⁷ and R⁸ attached to thesame carbon atom, together with that carbon atom, form an optionallysubstituted 3-7 membered cycloalkyl ring or an optionally substituted4-7 membered heterocycloalkyl ring; or R⁷ and R⁸ attached to adjacentcarbon atoms, together with those carbon atoms, form an optionallysubstituted 3-7 membered cycloalkyl ring or an optionally substituted4-7 membered heterocycloalkyl ring.

In some embodiments, R⁷ and R⁸ attached to the same carbon atom,together with that carbon atom, form a 3-7 membered cycloalkyl ring or4-7 membered heterocycloalkyl ring; or R⁷ and R⁸ attached to adjacentcarbon atoms, together with the atoms to which they are attached, form a3-7 membered cycloalkyl ring or 4-7 membered heterocycloalkyl ring.

In some embodiments, R⁷ or R⁸ are each independently H, —CH₃,-cyclopropyl, —CH₂CH3, or —CH(CH₃)₂.

In some embodiments, R⁷ and R⁸ attached to the same carbon atom,together with that carbon atom, form a cyclopropyl ring, a cyclobutylring, or azetidinyl ring.

In some embodiments, each R⁷ and each R⁸ is independently H, or a—C₁-C₆alkyl group optionally substituted with —OH; optionallysubstituted —OC₁-C₆alkyl; optionally substituted—(CH₂CH₂O)_(o)C₁-C₆alkyl wherein o is 1-10; or —C(O)NR^(c1)R^(d1)wherein R^(c1) and R^(d1) are independently H, optionally substituted—C₁-C₆alkyl, optionally substituted cycloalkyl, or optionallysubstituted heterocycloalkyl; or wherein or R^(c1) and R^(d1), togetherwith the N atom to which they are both attached, form an optionallysubstituted monocyclic or multicyclic heterocycloalkyl ring.

In some embodiments, the —C₁-C₆alkyl group is optionally substitutedwith —OH; —OC₁-C₆alkyl; —(CH₂CH₂O)_(o)C₁-C₆alkyl wherein o is 1-10; or—C(O)NR^(c1)R^(d1) wherein R^(c1) and R^(d1) are independently H,C₁-C₆alkyl, or 4-7 membered heterocycloalkyl; or wherein or R^(c1) andR^(d1), together with the N atom to which they are both attached, form amonocyclic or multicyclic 4-7 membered heterocycloalkyl ring optionallysubstituted with halo; —OC₁-C₆alkyl; or —C₁-C₆alkyl optionallysubstituted with —OH or —OC₁-C₆alkyl.

In some aspects, R⁷ and R⁸ together with the C atom to which they areboth attached form a cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl ring, each optionally substituted, each optionallysubstituted.

In some embodiments, R⁷ and R⁸ together with the C atom to which theyare both attached form a cycloalkyl ring, for example, a cyclopropylring, a cyclobutyl ring, or a cyclopentyl ring.

In some embodiments, R⁷ and R⁸ attached to the same carbon atom,together with that carbon atom, form an optionally substitutedcycloalkyl ring or an optionally substituted heterocycloalkyl ring.

In other embodiments, R⁷ and R⁸ attached to adjacent carbon atoms,together with those carbon atoms, form an optionally substitutedcycloalkyl ring or and optionally substituted heterocycloalkyl ring.

In other embodiments, R⁷ and R⁸ attached to the same carbon atom,together with that carbon atom, form an optionally substituted 3-7membered cycloalkyl ring or an optionally substituted 4-7 memberedheterocycloalkyl ring;

In other embodiments, R⁷ and R⁸ attached to adjacent carbon atoms,together with those carbon atoms, form an optionally substituted 3-7membered cycloalkyl ring or an optionally substituted 4-7 memberedheterocycloalkyl ring.

In other embodiments, R⁷ and R⁸ attached to adjacent carbon atoms,together with the atoms to which they are attached, form a 3-7 memberedcycloalkyl ring or 4-7 membered heterocycloalkyl ring.

In other embodiments, R⁷ and R⁸ attached to the same carbon atom,together with that carbon atom, form a cyclopropyl ring, a cyclobutylring, or azetidinyl ring.

In some aspects, an R⁷ and an R⁸ attached to adjacent carbon atoms,together with the C atoms to which they are attached, form a cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, eachoptionally substituted.

In some aspects, each R⁶ or R⁹ is independently H, D, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —OC₁-C₆alkyl, —C(O)R^(b), —C(O)OR^(a),—C(O)NR^(c)R^(d), —S(O)R^(b) or —S(O)₂R^(b), aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group,wherein the C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OC₁-C₆alkyl,aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl ring, is optionally substituted.

In some embodiments, R⁶ is H. In other embodiments, R⁶ is —C₁-C₆alkyl,for example, —CH₃ or —CH₂CH₃.

In some embodiments, R⁹ is H; optionally substituted —C₁-C₆alkyl;optionally substituted —C(O)OC₁-C₆alkyl; optionally substituted—SO₂C₁-C₆alkyl; optionally substituted —C(O)C₁-C₆alkyl; optionallysubstituted —C(O)NR^(c)R^(d); or wherein R⁹ together with either R⁷ orR⁸ form an optionally substituted heterocyclic alkylene.

In some embodiments, R⁹ is H; —C₁-C₆alkyl, optionally substituted withdeuterium; —C(O)OC₁-C₆alkyl; —SO₂C₁-C₆alkyl; —C(O)C₁-C₆alkyl; or whereinR⁹ together with either R⁷ or R⁸ forms an optionally heterocyclicalkylene.

In other embodiments, R⁹ is H; —C₁-C₆alkyl, optionally substituted withdeuterium; —C(O)OC₁-C₆alkyl; —SO₂C₁-C₆alkyl; —C(O)C₁-C₆alkyl.

In yet other embodiments, R⁹ is H; —CH₃; —CH₂CH₃, —CH₂CH₂CH₃, —CD₃,—C(O)OCH₃; —C(O)OC(CH₃)₃, —SO₂CH₃; or —C(O)CH₃.

In some aspects, R⁹ together with either an R⁷ or an R⁸ forms anoptionally substituted heterocyclic alkylene. In some embodiments, R⁹together with either R⁷ or R⁸ form a heterocyclic alkylene. In someembodiments, R⁹ together with either an R⁷ or an R^(8′) forms a C₃-C₉heterocyclic alkylene.

In some aspects, each R^(6A), R^(6B), R^(9A), or R^(9B) in Formula I isindependently H, D, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl,wherein the C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionallysubstituted.

In some aspects, R^(6A) and R^(6B) together with the N atoms to whichthey are attached form an optionally substituted heterocycloalkyl orheterocycloalkenyl ring.

In some aspects, R^(9A) and R^(9B) together with the N atoms to whichthey are attached form an optionally substituted heterocycloalkyl orheterocycloalkenyl ring;

In some aspects, each R^(a) in Formula I is independently H, D,—C(O)R^(b), —C(O)OR^(c), —C(O)NR^(c)R^(d), —P(OR^(c))₂, —P(O)R^(c)R^(b),—P(O)OR^(c)OR^(b), —S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b),—S(O)₂NR^(c)R^(d), —B(OR^(c))(OR^(b)), SiR^(b) ₃, —C₁-C₁₀alkyl, —C₂-C₁₀alkenyl, —C₂-C₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,heterocycloalkyl, or heterocycloalkenyl wherein said C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl,heteroaryl, heterocycloalkyl, or heterocycloalkenyl is optionallysubstituted.

In some embodiments, R^(a) is H, —C(O)R^(b), —C(O)NR^(c)R^(d),optionally substituted C₁-C₁₀alkyl, optionally substitutedC₂-C₁₀alkenyl, optionally substituted C₂-C₁₀ alkynyl, optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, or optionally substituted heterocycloalkyl

In some embodiments, R^(a) is H, —C(O)R^(b), —C(O)NR^(c)R^(d), oroptionally substituted C₁-C₁₀alkyl.

In some embodiments, R^(a) is H.

In some embodiments, R^(a) is —C(O)R^(b).

In some embodiments, R^(a) is —C(O)R^(b) wherein R^(b) is optionallysubstituted —C₁-C₆alkyl.

In some embodiments, R^(a) is —C(O)R^(b) wherein R^(b) is —C₁-C₆alkyl.

In some embodiments, R^(a) is —C(O)R^(b) wherein R^(b) is —CH₃.

In some embodiments, R^(a) is —C(O)NR^(c)R^(d).

In some embodiments, R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d)are independently H; optionally substituted —OC₁-C₆alkyl; optionallysubstituted cycloalkyl; optionally substituted —C₁-C₆alkyl, oroptionally substituted heterocycloalkyl.

In some embodiments, R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d)are independently H; optionally substituted 3-7 membered cycloalkyl;—OC₁-C₆alkyl; or —C₁-C₆alkyl optionally substituted with deuterium,halo, optionally substituted cycloalkyl, optionally substituted—OC₁-C₆alkyl, —NR^(c1)R^(d1) wherein R^(c1) and R^(d1) are independentlyH or optionally substituted —C₁-C₆alkyl, optionally substituted 4-7membered heterocycloalkyl, or optionally substituted 5-6 memberedheteroaryl; or optionally substituted 4-7 membered heterocycloalkyl.

In some embodiments, R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d)are independently H; 3-7 membered cycloalkyl; —C₁-C₆alkyl optionallysubstituted with deuterium, halo, —OC₁-C₆alkyl, cycloalkyl,—NR^(c1)R^(d1) wherein R^(c1) and R^(d1) are independently H or—C₁-C₆alkyl, 4-7 membered heterocycloalkyl (optionally substituted withhalo, —C₁-C₆alkyl, —OH, or —OC₁-C₆alkyl), or -5-6 membered heteroaryl,—OC₁-C₆alkyl; or -4-7 membered heterocycloalkyl optionally substitutedwith —C₁-C₆alkyl or —OH.

In some embodiments, R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d),together with the nitrogen atom to which they are both attached, form anoptionally substituted monocyclic or multicyclic heterocycloalkyl group.

In some embodiments, R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d),together with the nitrogen atom to which they are both attached, form amonocyclic or multicyclic heterocycloalkyl group optionally substitutedwith -halo, —OH, optionally substituted -4-7 membered heterocycle,optionally substituted 5-6 membered heteroaryl, optionally substituted—OC₁-C₆alkyl, optionally substituted —C₁-C₆alkyl; or —NR^(c1)R^(d1)wherein R^(c1) and R^(d1) are independently H or optionally substitutedC₁-C₆alkyl.

In some embodiments, R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d),together with the nitrogen atom to which they are both attached, form amonocyclic or multicyclic -4-10 membered heterocycloalkyl groupoptionally substituted with -halo, —OH, -4-7 membered heterocycle, 5-6membered heteroaryl, —OC₁-C₆alkyl, —C₁-C₆alkyl (optionally substitutedwith —OH, —OC₁-C₆alkyl, or NR^(c1)R^(d1) wherein R^(c1) and R^(d1) areindependently H or C₁-C₆alkyl); or —NR^(c1)R^(d1) wherein R^(c1) andR^(d1) are independently H or C₁-C₆alkyl.

In some embodiments, R^(a) is optionally substituted —C₁-C₁₀alkyl.

In some embodiments, R^(a) is —C₁-C₁₀alkyl optionally substituted with—C(O)NR^(c1)R^(d1), wherein R^(c1) and R^(d1) are independently H,optionally substituted C₁-C₆alkyl, or optionally substitutedheterocyclyl; or wherein or R^(c1) and R^(d1), together with the N atomto which they are both attached, form an optionally substitutedmonocyclic or multicyclic -4-10 membered heterocycloalkyl group;—NR^(c1)R^(d1) wherein R^(c1) and R^(d1) are independently H, optionallysubstituted C₁-C₆alkyl, optionally substituted cycloalkyl, or optionallysubstituted heterocycloalkyl; optionally substituted heteroaryl;—C(O)OH; or optionally substituted -heterocycloalkyl.

In some embodiments, R^(a) is —C₁-C₁₀alkyl optionally substituted with—C(O)NR^(c1)R^(d1), wherein R^(c1) and R^(d1) are independently H,C₁-C₆alkyl, or 4-7 membered heterocycloalkyl; or wherein or R^(c1) andR^(d1), together with the N atom to which they are both attached, form amonocyclic or multicyclic -4-10 membered heterocycloalkyl group(optionally substituted with halo, —OC₁-C₆alkyl, or —C₁-C₆alkyloptionally substituted with —OH or —OC₁-C₆alkyl); —NR^(c1)R^(d1) whereinR^(c1) and R^(d1) are independently H, or optionally substitutedC₁-C₆alkyl; —C₄-C₅heteroaryl; —C(O)OH; or -4-7 membered heterocycloalkyloptionally substituted with halo, C₁-C₆alkyl, or —OC₁-C₆alkyl.

In some embodiments, R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d)are independently H; —OCH₃, —CH₃, —CD₃, —CH₂CH₂OCH₃, —CH₂CH₃,—CH₂-cyclopropyl, -cyclobutyl, cyclopropyl, —CH(CH₃)₂, —CH₂—CH(CH₃)₂,—CH₂CH₂NH_(2J)—CH₂CH₂N(CH₃)₂, —CH₂CH₂NH(CH₃), —CH₂CHF₂,

In some embodiments, R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d),together with the nitrogen atom to which they are both attached, are

In some embodiments, R^(a) is —C₁-C₆alkyl optionally substituted with—N(CH₃)₂, —CO₂H, —CONH₂, —CON(CH₃)(CH₂CH₂OCH₃),

In some aspects, each R^(b) in Formula I is independently H, D, —C₁-C₆alkyl, —C₁-C₆ alkenyl, —C₂-C₆ alkynyl, aryl, cycloalkyl, cycloalkenyl,heteroaryl, heterocycloalkyl, or heterocycloalkenyl wherein the —C₁-C₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, aryl, cycloalkyl, cycloalkeneyl,heteroaryl, heterocycloalkyl, or heterocycloalkenyl is optionallysubstituted.

In some aspects, each R^(c) or R^(d) in Formula I is independently H, D,—C₁-C₁₀ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl,—O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl, wherein the C₁-C₁₀ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl areeach optionally substituted.

In some aspects, R^(c) and R^(d), together with the N atom to which theyare both attached, form an optionally substituted monocyclic ormulticyclic heterocycloalkyl, or optionally substituted monocyclic ormulticyclic heterocycloalkenyl group.

In some embodiments, compounds of Formula I are those having the FormulaIA-0:

In some embodiments, compounds of Formula I are those having the FormulaIA:

In some embodiments, the compounds of Formula IA are those wherein W¹ is—CH₂— and W³ is —O—, or W¹ is —O— and W³ is —CH₂—, or W¹ is —CH₂— and W³is —S—, or W¹ is —S— and W³ is —CH₂—, or W¹ is —CH₂— and W³ is—NR^(2B)—, or W¹ is —NR^(2B)— and W³ is —CH₂—, or W¹ is —CH₂— and W³ is—CH₂—.

In other embodiments, the compounds of Formula I are those havingFormula IA-1:

In some embodiments, the compounds of Formula IA-1 are those wherein W¹is —CH₂— or —O—.

In some embodiments, the compounds of Formula I are those having theFormula IA-2:

In some embodiments, the compound of formula IA-2 are those wherein W³is —CH₂— or —O—.

In some embodiments, the compounds of Formula I are those of FormulaIA-3 wherein W¹ is —CH₂— and W³ is O, or W¹ is —O— and W³ is —CH₂—, orW¹ is —CH₂— and W³ is —CH₂—:

In some embodiments, the compounds of Formula I are compound of FormulaIA-4:

or a pharmaceutically acceptable salt or solvate thereof; wherein W¹ is—CH₂— and W³ is O, or W¹ is —O— and W³ is —CH₂—, or W¹ is —CH₂— and W³is —CH₂₋; L³ is absent, or is —(CR⁴R⁵)_(p)—; L⁴ is absent, or—(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is absent, —CR^(4A)═CR^(4B)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—, —C(═O)O—,—NR^(6A)C(O), —C(═O)NR^(6A)—, —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—,—NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or—NR^(6A)S(O)₂—; L⁵ is absent, or is a 6- to 10-membered arylene, 5- to10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to12-membered cycloalkenylene, a 3- to 7-membered monocycliccycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-memberedmonocyclic heterocycloalkylene, or 6- to 12-membered bicyclicheterocycloalkylene group, wherein the 6- to 10-membered arylene, 5- to10-membered heteroaryl ene, a 3- to 12-membered cycloalkenylene, a 3- to12-membered cycloalkenylene, a 3- to 7-membered monocycliccycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-memberedmonocyclic heterocycloalkylene, or 6- to 12-membered bicyclicheterocycloalkylene group is optionally substituted; and L⁶ is absent,or is (CR⁷R⁸)_(s), —O(CR⁷R⁸)_(t), —NR⁹(CR⁷R⁸)_(t), —S(CR⁷R⁸)_(t),—S(O)(CR⁷R⁸)_(t), —S(O)₂(CR⁷R⁸)_(t), —NR^(9A)C(O)(CR⁷R⁸)_(t),—C(O)NR^(9A)(CR⁷R⁸)_(t), —R^(9A)C(O)O(CR⁷R⁸)_(t),—NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t), —NR^(9A)S(O)(CR⁷R⁸)_(t),—NR^(9A)S(O)₂(CR⁷R⁸)_(t); —CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t), —C(═O)(CR⁷R⁸>;—C(═O)(CR⁷R⁸)_(t)—O—, or —C(═O)(CR⁷R⁸)_(t)—NR⁶—.

In some embodiments of the compounds of Formula I or Formula IA-4, L³absent; L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is absent,—CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—,—C(═O)O—, —NR^(6A)C(O), —C(═O)NR^(6A)—, —NR^(6A)C(O)R^(6B)—,—OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—,—S(═O)₂NR^(6A)—, or —NR^(6A)S(O)₂—; and L⁵ is absent.

In some embodiments of the compounds of Formula I or Formula IA-4, L⁶ isabsent, or is —(CR⁷R⁸)_(s)—, —O(CR⁷R⁸)_(t)—, —NR⁹(CR⁷R⁸)_(t)—,—S(CR⁷R⁸)_(t)—, —S(O)(CR⁷R⁸)_(t)—, —S(O)₂(CR⁷R⁸)_(t)—,—NR^(9A)C(O)(CR⁷R⁸)_(t)—, —C(O)NR^(9A)(CR⁷R⁸)_(t)—,—R^(9A)C(O)O(CR⁷R⁸)_(t)—, —NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—,—NR^(9A)S(O)(CR⁷R⁸)_(t)—, —NR^(9A)S(O)₂(CR⁷R⁸)_(t)—;—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—, —C(═O)(CR⁷R⁸)_(t)—; —C(═O)(CR⁷R⁸)_(t)—O—,or —C(═O)(CR⁷R⁸)_(t)—NR⁶—.

In other embodiments of the compounds of Formula I or Formula IA-4, Q¹is —CR^(4A)═CR^(4B)—; and L⁶ is absent, —O(CR⁷R⁸)_(t), or—NR⁹(CR⁷R⁸)_(t);

In other embodiments of the compounds of Formula I or Formula IA-4, p=1;q=1-4; and t=1.

In other embodiments of the compounds for Formula I or Formula IA-4, L³absent; L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is absent,—CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—,—C(═O)O—, —NR^(6A)C(O), —C(═O)NR^(6A)—, —NR^(6A)C(O)R^(6B)—,—OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—,—S(═O)₂NR^(6A)—, or —NR^(6A)S(═O)₂—; L⁵ is a 6- to 10-membered arylene,5- to 10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a3- to 12-membered cycloalkenylene, a 3- to 7-membered monocycliccycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-memberedmonocyclic heterocycloalkylene, or 6- to 12-membered bicyclicheterocycloalkylene group, wherein the 6- to 10-membered arylene, 5- to10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to12-membered cycloalkenylene, a 3- to 7-membered monocycliccycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-memberedmonocyclic heterocycloalkylene, or 6- to 12-membered bicyclicheterocycloalkylene group is optionally substituted; and L⁶ is absent,or is (CR⁷R⁸)_(s).

In other embodiments, the compounds of Formula I or Formula IA-4 arethose wherein Q¹ is —CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(═O)—, —OC(═O)—, —C(═O)O—, —OC(═O)N(R^(6A))—, or —NR^(6A)C(O)O—; L⁵ isa 6- to 10-membered arylene, 5- to 10-membered heteroarylene, a 3- to7-membered monocyclic cycloalkylene, a 3- to 7-membered monocyclicheterocycloalkylene, wherein the 6- to 10-membered arylene, 5- to10-membered heteroarylene, a 3- to 7-membered monocyclic cycloalkylene,a 3- to 7-membered monocyclic heterocycloalkylene is optionallysubstituted; and L⁶ is absent, or is (CR⁷R⁸)_(s).

In some embodiments, the compounds of Formula I or Formula IA-4 arethose wherein L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)— wherein p=1; q=1-3, Q¹ isabsent, or —CR^(4A)═CR^(4B)—; L⁶ is (CR⁷R⁸)_(s) wherein s=1-2,—O(CR⁷R⁸)_(t), —NR⁹(CR⁷R⁸)_(t), —S(CR⁷R⁸)_(t), —S(O)(CR⁷R⁸)_(t), or—S(O)₂(CR⁷R⁸)_(t), wherein t=1.

In some embodiments, the compounds of Formula I are those of FormulaIA-5

wherein X is O, NR⁹, CR⁷R⁸, S, S(O), SO₂; R is halo or C₁-C₆alkyl;

represents a carbon-carbon single bond in which each carbon atom in thebond is substituted with R⁴ and R⁵, an (E)-carbon-carbon double bondsubstituted with R^(4A) and R^(4B), or a (Z)-carbon-carbon double bondsubstituted with R^(4A) and R^(4B); and R^(a*) is R^(a) wherein R^(a) isH, —C(O)R^(b), —C(O)OR^(c), —C(O)NR^(c)R^(d), P(OR^(c))₂,P(O)R^(c)R^(b), P(O)OR^(c)OR^(b), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), S(O)₂NR^(c)R^(d), B(OR^(c))(OR^(b)), SiR^(b) ₃, C₁-C₁₀alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, wherein said C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionallysubstituted.

In some embodiments of the compound Formula IA-5,

represents a carbon-carbon single bond in which each carbon atom in thebond is substituted with R⁴ and R⁵.

In other embodiments of the compound Formula IA-5,

represents a carbon-carbon double bond.

In some embodiments of the compound Formula IA-5, X is O, NR⁹, or CR⁷R⁸.

In some embodiments of the compound Formula IA-5, R^(a*) is R^(a)wherein R^(a) is H, —C(O)R^(b), —C(O)NR^(c)R^(d), or optionallysubstituted C₁-C₁₀alkyl, optionally substituted C₂-C₁₀alkenyl,optionally substituted C₂-C₁₀ alkynyl, optionally substituted aryl,optionally substituted cycloalkyl, optionally substituted heteroaryl, oroptionally substituted heterocycloalkyl.

In some aspects, the compounds of Formula I are those of Formula IA-6:

or a pharmaceutically acceptable salt or solvate thereof; wherein X is—O—, —NR⁹—, or —CR⁷R⁸—; and W¹ is —CH₂— and W³ is O, or W¹ is —O— and W³is —CH₂—, or W¹ is —CH₂— and W³ is —CH₂; R^(a*) is R^(a).

In some embodiments, the compounds of Formula IA-6 are those wherein Xis —CR⁷R⁸—.

In other embodiments, the compounds of Formula IA-6 are those wherein Xis —O—.

In some embodiments, the compounds of Formula IA-6 are those wherein Xis —NR⁹—.

In some embodiments X is —NR⁹— wherein R⁹ is H; optionally substituted—C₁-C₆alkyl; optionally substituted —C(O)OC₁-C₆alkyl; optionallysubstituted —SO₂C₁-C₆alkyl; optionally substituted —C(O)C₁-C₆alkyl;optionally substituted —C(O)NR^(c)R^(d); or wherein R⁹ together witheither R⁷ or R⁸ form an optionally substituted C₁-C₆alkylene group.

In other embodiments, X is —NR⁹— wherein R⁹ is H; —C₁-C₆alkyl,optionally substituted with deuterium; —C(O)OC₁-C₆alkyl; —SO₂C₁-C₆alkyl;—C(O)C₁-C₆alkyl; or wherein R⁹ together with either R⁷ or R⁸ form aC₁-C₆alkylene group.

In some embodiments, the compounds of Formula IA-6 are those having thestructure (LA-7):

-   -   wherein W¹ is —CH₂— and W³ is —O—; or W¹ is —O— and W³ is —CH₂—;        or W¹ is —CH₂— and W³ is —CH₂—.

In some embodiments, the compounds of Formula IA-7 are those wherein W¹is —CH₂— and W³ is —CH₂—.

In some embodiments, the compounds of Formula I are those of FormulaIA-8

wherein X is O, NR⁹, CR⁷R⁸, S, S(O), SO₂; W¹ is —CH₂— and W³ is O, or W¹is —O— and W³ is —CH₂—, or W¹ is —CH₂— and W³ is —CH₂—;

is halo or C₁-C₆alkyl; represents a carbon-carbon single bond in whicheach carbon atom in the bond is substituted with R⁴ and R⁵, an(E)-carbon-carbon double bond, or a (Z)-carbon-carbon double bond; andR^(a*) is R^(a) wherein R^(a) is H, —C(O)R^(b), —C(O)OR^(c),—C(O)NR^(c)R^(d), P(OR^(c))₂, P(O)R^(c)R^(b), P(O)OR^(c)OR^(b),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), S(O)₂NR^(c)R^(d),B(OR^(c))(OR^(b)), SiR^(b) ₃, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein saidC₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl is optionally substituted; and R^(c)* isR^(c) wherein R^(c) is H, D, —C₁-C₁₀ alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein saidC₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl,aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl are each optionally substituted.

In some embodiments of the compound Formula IA-8,

represents a carbon-carbon single bond in which each carbon atom in thebond is substituted with R⁴ and R⁵.

In other embodiments of the compound Formula IA-8,

represents a carbon-carbon double bond.

In other embodiments of the compound Formula IA-8,

represents a (E)-carbon-carbon double bond substituted with R^(4A) andR^(4B).

In some embodiments of the compound of Formula IA-8, R^(a)* is R^(a) andR^(c)* is R^(c).

In other embodiments of the compound Formula IA-8, R^(a)* is R^(a)wherein R^(a) is H, —C(O)R^(b), —C(O)OR^(c), —C(O)NR^(c)R^(d),—S(O)₂R^(b), or optionally substituted C₁-C₁₀alkyl; and R^(c)* is R^(c)wherein R^(c) is H or optionally substituted C₁-C₁₀alkyl.

In other embodiments of the compound Formula IA-8, R is —Cl.

In other embodiments of the compound Formula IA-8, each R⁴ and R⁵ isindependently H or C₁-C₆alkyl.

In some embodiments of the compound Formula IA-8, X is O, NR⁹, or CR⁷R⁸.

In some aspects, the compounds of Formula I are those of Formula IA-9:

or a pharmaceutically acceptable salt or solvate thereof; wherein X is—O—, —NR⁹—, or —CR⁷R⁸—; and ¹ is —CH₂— and W³ is O, or W¹ is —O— and W³is —CH₂—, or W¹ is —CH₂— and W³ is —CH₂₋; R^(a)* is R^(a) and R^(c)* isR^(c).

In other embodiments of the compound Formula IA-9, R^(a)* is R^(a)wherein R^(a) is H, —C(O)R^(b), —C(O)OR^(c), —C(O)NR^(c)R^(d),—S(O)₂R^(b), or optionally substituted C₁-C₁₀alkyl; and R^(c)* is R^(c)wherein R^(c) is H or optionally substituted C₁-C₁₀alkyl.

In some embodiments, the compounds of Formula IA-9 are those wherein Xis —CR⁷R⁸—.

In other embodiments, the compounds of Formula IA-9 are those wherein Xis —O—.

In some embodiments, the compounds of Formula IA-9 are those wherein Xis —NR⁹—.

In some embodiments, X is —NR⁹— wherein R⁹ is H; optionally substituted—C₁-C₆alkyl; optionally substituted —C(O)OC₁-C₆alkyl; optionallysubstituted —SO₂C₁-C₆alkyl; optionally substituted —C(O)C₁-C₆alkyl;optionally substituted —C(O)NR^(c)R^(d); or wherein R⁹ together witheither R⁷ or R⁸ form an optionally substituted C₁-C₆alkylene group.

In other embodiments, X is —NR⁹— wherein R⁹ is H; —C₁-C₆alkyl,optionally substituted with deuterium; —C(O)OC₁-C₆alkyl; —SO₂C₁-C₆alkyl;—C(O)C₁-C₆alkyl; or wherein R⁹ together with either R⁷ or R⁸ form aC₁-C₆alkylene group.

In some embodiments, the compounds of Formula IA-9 are those having thestructure (IA-10):

In some aspects, the disclosure is directed to compounds of Formula II:

or a pharmaceutically acceptable salt or solvate thereof.

In some aspects, Z in Formula II is C or N. In some embodiments, Z is C.In other embodiments, Z is N.

In some aspects, Q in Formula II is —O—, —S—, —S(O)—, or —S(O)₂—. Insome embodiments, Q is —O—. In some embodiments, Q is —S—. In someembodiments, Q is —S(O)—. In some embodiments, Q is —S(O)₂—.

In some aspects, the moiety -W¹-W²-W³ in Formula II is—CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—, —O—CR^(2B)R^(2C)—CR²R^(2A)—,—CR²R^(2A)—CR^(2B)R^(2C)—O—, —S—CR^(2B)R^(2C)—CR²R^(2A), or—CR²R^(2A)—CR^(2B)R^(2C)—S—.

In some embodiments, the moiety -W¹-W²-W³ in Formula II is—CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—. In some embodiments, the moiety-W¹-W²-W³ in Formula II is —O—CR^(2B)R^(2C)—CR²R^(2A)—. In someembodiments, the moiety -W¹-W²-W³ in Formula II—CR²R^(2A)—CR^(2B)R^(2C)—O—. In some embodiments, the moiety -W¹-W²-W³in Formula II is —S—CR^(2B)R^(2C)—CR²R^(2A). In some embodiments, themoiety -W¹-W²-W³ in Formula II is —CR²R^(2A)—CR^(2B)R^(2C)—S—.

In some aspects, L¹ in Formula II is —C₁-C₆alkylene-, for example,—C₁alkylene, —C₂alkylene, —C₃alkylene, —C₄alkylene, —C₅alkylene, or—C₆alkylene, wherein the C₁-C₆alkylene is optionally substituted with 1,2, or 3 substituents independently selected from halo, oxo, CN, OR^(a1),SR^(a1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), and NR^(c1)S(O)₂R^(b1).In some embodiments, L¹ in Formula II is —C₁alkylene. In someembodiments, L¹ in Formula II is —CH₂—.

In some aspects, L² in Formula II is C₃-C₇cycloalkylene,C₄-C₇heterocycloalkylene, or heteroarylene; wherein theC₃-C₇cycloalkylene, C₄-C₇heterocycloalkylene, or heteroarylene isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, oxo, CN, NO₂, N₃, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), P(O)OR^(e1)OR^(f1), S(O)₂R^(a2),NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, L² in Formula II is C₃-C₇cycloalkylene, forexample, C₃cycloalkylene, C₄cycloalkylene, C₅cycloalkylene,C₆cycloalkylene, or C₇cycloalkylene. In some embodiments, L² isC₄cycloalkylene. In some embodiments, L² is cyclobutylen-yl.

In some embodiments, L² in Formula II is C₄-C₇heterocycloalkylene, forexample, C₄heterocycloalkylene, C₅heterocycloalkylene,C₆heterocycloalkylene, or C₇heterocycloalkylene. In some embodiments, L²in Formula II is C₄heterocycloalkylene. In some embodiments, L² ispyrrolidinyl.

In other embodiments, L² in Formula II is heteroarylene. In someembodiment, the heteroarylene is pyrazolyl.

In some aspects, L³ in Formula II is absent, or is —(CR⁴R⁵)_(p)—,—(CR⁴R⁵)_(p)O—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—,—C(═O)O—, —NR^(6A)C(O), —C(═O)NR^(6A)—, —OC(═O)N(R^(6A))—,—NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or—NR^(6A)S(O)₂—.

In some embodiments, L³ in Formula II is absent. In some embodiments, L³is —(CR⁴R⁵)_(p)—. In some embodiments, L³ is —(CR⁴R⁵)_(p)O—. In someembodiments, L³ is —O—. In some embodiments, L³ is —S—. In someembodiments, L³ is —S(O)—. In some embodiments, L³ is —S(O)₂—. In someembodiments, L³ is —C(═O)—. In some embodiments, L³ is —NR⁶—. In someembodiments, L³ is —OC(═O)—. In some embodiments, L³ is —C(═O)O—. Insome embodiments, L³ is —NR^(6A)C(O). In some embodiments, L³ is—C(═O)NR^(6A)—. In some embodiments, L³ is —OC(═O)N(R^(6A))—. In someembodiments, L³ is —NR^(6A)C(O)O—. In some embodiments, L³ is—S(═O)NR^(6A)—. In some embodiments, L³ is —NR^(6A)S(O)—. In someembodiments, L³ is —S(═O)₂NR^(6A)—. In some embodiments, L³ is—NR^(6A)S(O)₂—.

In some aspects, L⁴ in Formula II is absent, or is—(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —CR^(4A)═CR^(4B)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—, —C(═O)O—, —NR^(6A)C(O),—C(═O)NR^(6A)—, —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—,—S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or —NR^(6A)S(O)₂—; or is—(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—.

In some embodiments, L⁴ in Formula II is absent. In other embodiments,L⁴ in Formula II is —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—. Inother embodiments, L⁴ in Formula II is —(CR⁴R⁵)_(p)—O—(CR⁴R⁵)_(q)—. Inother embodiments, L⁴ in Formula II is —(CR⁴R⁵)_(p)—S—(CR⁴R⁵)_(q)—. Inother embodiments, L⁴ in Formula II is —(CR⁴R⁵)_(p)—S(O)—(CR⁴R⁵)_(q)—.In other embodiments, L⁴ in Formula II is—(CR⁴R⁵)_(p)—S(O)₂—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ in Formula IIis —(CR⁴R⁵)_(p)—C(═O)—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ in FormulaII is —(CR⁴R⁵)_(p)—NR⁶—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ in FormulaII is —(CR⁴R⁵)_(p)—OC(═O)—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ inFormula II is —(CR⁴R⁵)_(p)—C(═O)O—(CR⁴R⁵)_(q)—. In other embodiments, L⁴in Formula II is —(CR⁴R⁵)_(p)—NR^(6A)C(O)—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula II is —(CR⁴R⁵)_(p)—C(═O)NR^(6A)—(CR⁴R⁵)_(q)—.In other embodiments, L⁴ in Formula II is—(CR⁴R⁵)_(p)—NR^(6A)C(O)R^(6B)—CR⁴R⁵)_(q)—. In other embodiments, L⁴ inFormula II is —(CR⁴R⁵)_(p)—OC(═O)N(R^(6A))—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula II is —(CR⁴R⁵)_(p)—NR^(6A)C(O)O—(CR⁴R⁵)_(q)—.In other embodiments, L⁴ in Formula II is—(CR⁴R⁵)_(p)—S(═O)NR^(6A)—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ inFormula II is —(CR⁴R⁵)_(p)—NR^(6A)S(O)—(CR⁴R⁵)_(q)—. In otherembodiments, L⁴ in Formula II is—(CR⁴R⁵)_(p)—S(═O)₂NR^(6A)—(CR⁴R⁵)_(q)—. In other embodiments, L⁴ inFormula II is —(CR⁴R⁵)_(p)—NR^(6A)S(O)₂—(CR⁴R⁵)_(q)—. In someembodiments, L⁴ is —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—.

In some aspects, L⁵ in Formula II is absent, or is C₁-C₆ alkylene, C₂-C₆alkenylene, C₂₋₆ alkynylene, a 6- to 10-membered arylene, 5- to10-membered heteroarylene, a 5- to 12-membered spirocycloalkylene, a 5-to 12-membered spiroheterocycloalkylene, a 3- to 12-memberedcycloalkenylene, a 3- to 7-membered monocyclic cycloalkylene, or a 6- to12-membered bicyclic cycloalkylene, or a 3- to 7-membered monocyclicheterocycloalkylene or a 6 to 12-membered bicyclic heterocycloalkylenegroup, wherein the heteroarylene, spiroheterocycloalkylene orheterocycloalkylene group have 1, 2, 3 or 4, heteroatoms independentlyselected from O, N or S; wherein the cycloalkylene, spirocycloalkylene,spiroheterocycloalkylene, and heterocycloalkylene groups may include aC═O group; wherein the spiroheterocycloalkylene, and heterocycloalkylenegroups may include a S═O or SO₂; wherein said C₁-C₆ alkylene, C₂-C₆alkenylene, C₂-C₆ alkynylene, cycloalkylene, spirocycloalkylene,heterocycloalkylene, spiroheterocycloalkylene, arylene or heteroaryleneare optionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, C₁-C₆ alkyl NR^(c3)R^(d3), C₂-C₆ alkenyl NR^(c3)R^(d3), C₂-C₆alkynyl NR^(c3)R^(d3), OC₂-C₆ alkyl NR^(c3)R^(d3), CN, NO₂, N₃, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), —CH₂C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3),C(═NR^(g1))NR^(c2)R^(d2), NR^(c3)C(═NR^(g1))NR^(c3)R^(d3), P(R^(f2))₂,P(OR^(e2))₂, P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3).

In some embodiments, L⁵ in Formula II is absent. In other embodiments,L⁵ in Formula II is C₁-C₆ alkylene, for example, C₁alkylene, C₂alkylene,C₃alkylene, C₄alkylene, C₅alkylene, or C₆alkylene.

In other embodiments, L⁵ in Formula II is C₂-C₆ alkenylene, for example,C₂alkenylene, C₃alkenylene, C₄alkenylene, C₅alkenylene, or C₆alkenylene.

In other embodiments, L⁵ in Formula II is C₂-C₆ alkynylene, for example,C₂alkynylene, C₃alkynylene, C₄alkynylene, C₅alkynylene, or C₆alkynylene.

In other embodiments, L⁵ in Formula II is a 6- to 10-membered arylene,for example phenylene or naphthylene. In some embodiments, L⁵ in FormulaII is a phenylene.

In other embodiments, L⁵ in Formula II is a 5- to 10-memberedheteroarylene, for example, pyrazolyl, thiazolyl, imidazolyl, orpyridinyl. In some embodiments, L⁵ in Formula II is pyrazolyl. In someembodiments, L⁵ in Formula II is thiazolyl. In some embodiments, L⁵ inFormula II is imidazolyl. In some embodiments, L⁵ in Formula II ispyridinyl.

In other embodiments, L⁵ in Formula II is a 5- to 12-memberedspirocycloalkylene, for example, spiro[3.4]octane, or spiro[3.3]heptane.

In other embodiments, L⁵ in Formula II is a 5- to 12-memberedspiroheterocycloalkylene, for example, 2,6-diazaspiro[3.4]octane,2-azaspiro[3.4]octane, or 2-azaspiro[3.3]heptane. In some embodiments,L⁵ in Formula II is 2,6-diazaspiro[3.4]octane. In some embodiments, L⁵in Formula II is 2-azaspiro[3.4]octane. In some embodiments, L⁵ inFormula II is 2-azaspiro[3.3]heptane.

In other embodiments, L⁵ in Formula II is a 3- to 12-memberedcycloalkenylene, for example, cyclohexenyl.

In other embodiments, L⁵ in Formula II is a 3- to 7-membered monocycliccycloalkylene, for example, cyclopentanyl, cyclohexanyl, and the like.In some embodiments, L⁵ in Formula II is cyclopentanyl.

In other embodiments, L⁵ in Formula II is a 6- to 12-membered bicycliccycloalkylene.

In other embodiments, L⁵ in Formula II is a 3- to 7-membered monocyclicheterocycloalkylene group, for example, pyrrolidinyl, tetrahydrofuranyl,piperidinyl, piperazinyl, and the like. In some embodiments, L⁵ inFormula II is pyrrolidinyl. In some embodiments, L⁵ in Formula II istetrahydrofuranyl. In some embodiments, L⁵ in Formula II is piperidinyl.In some embodiments, L⁵ in Formula II is piperazinyl.

In other embodiments, L⁵ in Formula II is a 6- to 12-membered bicyclicheterocycloalkylene group.

In some aspects, L⁶ in Formula II is absent, or is (CR⁷R⁸)_(s),(CR⁷R⁸)_(s)O(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)S(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR^(9A)C(O)(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)OC(O)NR^(9A)(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR^(9A)C(O)O(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)NR^(9A)S(O)(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR^(9A)S(O)₂(CR⁷R⁸)_(t);—(CR⁷R⁸)_(s)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t);—(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—, or —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—.

In some embodiments, L⁶ in Formula II is absent. In other embodiments,L⁶ in Formula II is (CR⁷R⁸)_(s). In other embodiments, L⁶ in Formula IIis (CR⁷R⁸)_(s)O(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula II is(CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula II is(CR⁷R⁸)_(s)S(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula II is(CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula II is(CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t). In other embodiments, L⁶ in Formula II is(CR⁷R⁸)_(s)NR^(9A)C(O)(CR⁷R⁸)_(t). In other embodiments, L⁶ in FormulaII is (CR⁷R⁸)_(s)OC(O)NR^(9A)(CR⁷R⁸)_(t). In other embodiments, L⁶ inFormula II is (CR⁷R⁸)_(s)NR^(9A)C(O)O(CR⁷R⁸)_(t). In other embodiments,L⁶ in Formula II is (CR⁷R⁸)_(s)NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t). In otherembodiments, L⁶ in Formula II is (CR⁷R⁸)_(s)NR^(9A)S(O)(CR⁷R⁸)_(t). Inother embodiments, L⁶ in Formula II is(CR⁷R⁸)_(s)NR^(9A)S(O)₂(CR⁷R⁸)_(t). In other embodiments, L⁶ in FormulaII is —(CR⁷R⁸)_(s)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t). In other embodiments, L⁶in Formula II is (CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t). In other embodiments, L⁶in Formula II is —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—. In other embodiments,L⁶ in Formula II is —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—.

In some aspects, in Formula II, n=0-3. In some embodiments, n=0. Inother embodiments, n=1. In other embodiments, n=2. In other embodiments,n=3.

In some aspects, in Formula II, m=0-2. In some embodiments, m=0. Inother embodiments, m=1. In other embodiments, m=2.

In some aspects, in Formula II, o=1-3. In some embodiments, o=0. Inother embodiments, o=1. In other embodiments, o=2. In other embodiments,o=3.

In some aspects, in Formula II, p=0-4. In some embodiments, p=0. Inother embodiments, p=1. In other embodiments, p=2. In other embodiments,p=3. In other embodiments, p=4.

In some aspects, in Formula II, q=0-3. In some embodiments, q=0. Inother embodiments, q=1. In other embodiments, q=2. In other embodiments,q=3.

In some aspects, in Formula II, s=0-3. In some embodiments, s=0. Inother embodiments, s=1. In other embodiments, s=2. In other embodiments,s=3.

In some aspects, in Formula II, t=0-4. In some embodiments, t=0. Inother embodiments, t=1. In other embodiments, t=2. In other embodiments,t=3. In other embodiments, t=4.

In some aspects, each R in Formula II is independently selected fromhalo, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,—(CH₂CH₂O)_(o)R^(a), C₁-C₆haloalkoxy, C₃-C₆cycloalkyl, OR^(a), SR^(a),C(O)R^(b), C(O)OR^(a), NR^(c)R^(d), C(O)NR^(c)R^(d), and S(O)₂R^(a);wherein said C₁-C₆alkyl or C₃-C₆cycloalkyl is optionally substituted by1, 2, or 3 substituents independently selected from halo, CN, OR^(a1),NR^(c1)R^(d1) and C(O)NR^(c1)R^(d1).

In some embodiments, R is halo, for example, Cl or F. In someembodiments, R is —SR^(a), for example —SCH₃.

In some aspects, each R¹ in Formula II is independently selected fromhalo, —CN, Nitro, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,C₁-C₆haloalkyl, —(CH₂CH₂O)_(o)R^(a), —C₁-C₆alkylC₃-C₇cycloalkyl, OR^(a),SR^(a), NR^(c)R^(d), C(O)R^(b), OC(O)R^(b), C(O)OR^(a), C(O)NR^(c)R^(d),or S(O)₂R^(a); aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl,cycloalkyl, or heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl or heterocycloalkyl group have 1, 2, 3 or 4,heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O orSO₂; wherein said C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, CN,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), P(OR^(e3))₂,P(O)R^(e3)R^(G), P(O)OR^(e3)OR^(G), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).

In some embodiments, R¹ in Formula II is halo, for example, Cl or F. Inother embodiments, R¹ in Formula II is —C₁-C₆haloalkyl, for example—CF₃. In other embodiments, R¹ in Formula II is —C₁-C₆alkyl, forexample, —C₆alkyl, —C₅alkyl, —C₄alkyl, —C₃alkyl, —C₂alkyl, —C₁alkyl. Insome embodiments, R¹ in Formula II is —C₁alkyl substituted with —CN. Inother embodiments, R¹ in Formula II is cycloalkyl, for example,cyclopropane, cyclobutane, cyclopentane, and the like. In otherembodiments, R¹ in Formula II is cyclopropane substituted with —CN.

In some aspects, R² and R^(2A) in Formula II are each independently H,halo, OR^(a), C₁-C₆alkyl, C₁-C₆haloalkyl. In some embodiments, R² andR^(2A) in Formula II are each H.

In other aspects, R² and R^(2A) that are attached to the same carbonatom, together with the carbon atom to which they are both attached,form an optionally substituted C₃-C₆cycloalkyl ring. In someembodiments, R² and R^(2A) that are attached to the same carbon atom,together with the carbon atom to which they are both attached, form acyclopropane ring.

In some aspects, R² and R^(2a) in Formula II are each independently H,halo, OR^(a), C₁-C₆alkyl, C₁-C₆haloalkyl. In some embodiments, R² andR^(2a) in Formula II are each H.

In other aspects, R² and R^(2a) that are attached to the same carbonatom, together with the carbon atom to which they are both attached,form an optionally substituted C₃-C₆cycloalkyl ring. In someembodiments, R² and R^(2a) that are attached to the same carbon atom,together with the carbon atom to which they are both attached, form acyclopropane ring.

In some aspects, R^(2B) and R^(2C) in Formula II are each independentlyH, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments, R^(2B) and R^(2C)in Formula II are each H.

In some aspects, R^(2B) and R^(2C) may, together with the carbon atom towhich they are both attached, form an optionally substitutedC₃-C₆cycloalkyl ring. In some embodiments, R^(2B) and R^(2C) that areattached to the same carbon atom together with the carbon atom to whichthey are both attached, form a cyclopropane ring.

In some aspects, R³ in Formula II is H, —C₁-C₆alkyl, —C₃-C₆alkenyl,—C₃-C₆alkynyl, —(CH₂CH₂O)_(o)R^(a), —C₃-C₇cycloalkyl,—C₃-C₇heterocycloalkyl, —C₁-C₆alkylC₃-C₇cycloalkyl,—C₁-C₆alkylC₃-C₇heterocycloalkyl, C(O)R^(b), C(O)OR^(a), orC(O)NR^(c)R^(d); wherein the C₁-C₆alkyl, —C₃-C₆alkenyl, —C₃-C₆alkynyl,cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or3 substituents independently selected from OH, halo, C₁₋₆ alkyl, CN,—OP(O)OR^(e3)OR^(G), and OR^(a4).

In some embodiments, R³ in Formula II is H. In other embodiments, R³ inFormula II is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, C₁alkyl, —CH₃, and the like.

In some aspects, R⁴ and R⁷ in Formula II are independently selected fromH, halo, OH, CN, NO₂, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—C₁-C₆haloalkyl, —(CH₂CH₂O)_(o)R^(a), C₃-C₇cycloalkyl,—C₁-C₆alkylC₃-C₇cycloalkyl, cyanoC₁-C₆alkyl-, heterocycloalkyl,C₁-C₆alk-NRHC¹, OR^(a), SR^(a), NR^(c)R^(d), C(O)R^(b), OC(O)R^(a),C(O)OR^(a), C(O)NR^(c)R^(d), and S(O)₂R^(a), wherein said C₁-C₆alkyl,C₃-C₇cycloalkyl, heterocycloalkyl, or —C₁-C₆alkylC₃-C₇cycloalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, CN,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), P(OR^(e3))₂,P(O)R^(e3)R^(G), P(O)OR^(e3)OR^(G) S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).

In some embodiments, R⁴ is Formula II is H. In other embodiments, R⁴ inFormula II is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, C₁alkyl, —CH₃, and the like. In other embodiments, R⁴is Formula II is —OR^(a), for example, —OCH₃.

In some embodiments, R⁷ in Formula II is H. In other embodiments, R⁷ inFormula II is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, C₁alkyl, —CH₃, and the like. In other embodiments, R⁷is Formula II is —OR^(a), for example, —OCH₃.

In some aspects, R^(4A) and R^(4B) in Formula II are independentlyselected from H, Me, CF₃ and F. In some embodiments, R^(4A) is H. Insome embodiments, R^(4B) is H.

In some aspects, R⁵ and R⁸ in Formula II are independently selected fromH, halo, OH, CN, NO₂, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—C₁-C₆haloalkyl, —(CH₂CH₂O)_(o)R^(a), —C₁-C₆alkylC₃-C₇cycloalkyl,cyanoC₁-C₆alkyl-, C₁-C₆alk-NR^(c)R^(d), OR^(c), SR^(C), NR^(c)R^(d),C(O)R^(c), OC(O)R^(c), C(O)OR^(c), C(O)NR^(c)R^(d), S(O)R^(c),S(O)₂R^(C), aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl,cycloalkyl, and heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl or heterocycloalkyl group have 1, 2, 3 or 4,heteroatoms independently selected from O, N and S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O orSO₂, wherein said C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, or—C₁-C₆alkylC₃-C₇cycloalkyl, cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, and heterocycloalkyl is optionally substitutedwith 1, 2, or 3 substituents independently selected from R¹⁰, halo,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, CN, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), P(OR^(e3))₂,P(O)R^(e3)R^(G), P(O)OR^(e3)OR^(G) S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).

In some embodiments, R⁵ in Formula II is H. In other embodiments, R⁵ inFormula II is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, C₁alkyl, —CH₃, and the like. In other embodiments, R⁵in Formula II is —OR^(a), for example, —OCH₃.

In some embodiments, R⁸ in Formula II is H. In other embodiments, R⁸ inFormula II is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, C₁alkyl, —CH₃, and the like. In other embodiments, R⁸in Formula II is —OR^(a), for example, —OCH₃.

In some embodiments, R⁴ and R⁵ in Formula II, together with the carbonatom to which they are both attached form a 3, 4, 5, 6, or 7-memberedcycloalkyl, heterocycloalkyl or spiroheterocycloalkyl ring, eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C₁-C₆ haloalkyl,CN, and NO₂.

In some embodiments, R⁷ and R⁸ in Formula II, together with the carbonatom to which they are both attached form a 3, 4, 5, 6, or 7-memberedcycloalkyl, heterocycloalkyl or spiroheterocycloalkyl ring, eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C₁₋₆ haloalkyl,CN, and NO₂.

In some aspects, R⁶ and R⁹ in Formula II are independently selected fromH, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₁-C₆haloalkyl,—(CH₂CH₂O)_(o)R^(a), —C₁-C₆alkylC₃-C₇cycloalkyl, cyanoC₁-C₆alkyl-,C₁-C₆alk-NR^(c)R^(d), C(O)R^(b), C(O)OR^(a), C(O)NR^(c)R^(d), S(O)R^(b)S(O)₂R^(b), aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl,cycloalkyl, and heterocycloalkyl group, wherein the heteroaryl,spiroheterocycloalkyl or heterocycloalkyl group have 1, 2, 3 or 4,heteroatoms independently selected from O, N or S, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkylgroups may include a C═O group, and further wherein thespiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O orSO₂, wherein said C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—C₁-C₆alkylC₃-C₇cycloalkyl, aryl, heteroaryl, cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, CN, N₃,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), P(OR^(e3))₂,P(O)R^(e3)R^(G), P(O)OR^(e3)OR^(G) S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).

In some embodiments, R⁶ in Formula II is H. In other embodiments, R⁶ inFormula II is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, or C₁alkyl.

In some embodiments, R⁹ in Formula II is H. In other embodiments, R⁶ inFormula II is —C₁-C₆alkyl, for example, C₆alkyl, C₅alkyl, C₄alkyl,C₃alkyl, C₂alkyl, or C₁alkyl.

In some aspects, R¹⁰ in Formula II is aryl, heteroaryl, spirocycloalkyl,spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl group, whereinthe heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group have 1,2, 3 or 4, heteroatoms independently selected from O, N or S, whereinthe cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, andheterocycloalkyl groups may include a C═O group, and further wherein thespiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O orSO₂, wherein said aryl, cycloalkyl, cycloalkenyl, spirocycloalkyl,spiroheterocycloalkyl, heteroaryl, and heterocycloalkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —CH₂CH₂OR^(a), CN, N₃,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), P(OR^(e3))₂,P(O)R^(e3)R^(G), P(O)OR^(e3)OR^(G), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).

In some aspects R^(6A), R^(6B), R^(9A), and R^(9B) in Formula II areeach independently H, C i-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—(CH₂CH₂O)_(o)R^(a), C₃-C₇cycloalkyl, —C₁-C₆alkylC₃-C₇cycloalkyl,C₄-C₇heterocycloalkyl, —C₁-C₆alkylC₄-C₇heterocycloalkyl, wherein saidC₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C₃-C₇cycloalkyl,—C₁-C₆alkylC₃-C₇cycloalkyl, —C₄-C₇heterocycloalkyl,—C₁-C₆alkylC₃-C₇heterocycloalkyl is optionally substituted with 1, 2, or3 substituents independently selected from halo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, CN, N₃, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)C(O)OR^(a4), P(OR^(e3))₂, P(O)R^(e3)R^(G), P(O)OR^(e3)OR^(f3),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4).

In some embodiments, R^(6A) and R^(6B) in Formula II, together with theN atom to which they are attached form a 5, 6, 7, 8 or 9-memberedheterocycloalkyl ring or spiroheterocycloalkyl ring, each optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C₁-C₆ haloalkyl,CN, and NO₂.

In some embodiments, R^(9A) and R^(9B) in Formula II, together with theN atom to which they are attached form a 5, 6, 7, 8 or 9-memberedheterocycloalkyl ring or spiroheterocycloalkyl ring, each optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C₁-C₆ haloalkyl,CN, and NO₂.

In some aspects, R^(a), R^(a1), R³², R^(a3), and R^(a4) in Formula IIare independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereinsaid C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy.

In some embodiments, R^(a) is H. In other embodiments, R^(a) is —C₁-C₆alkyl, for example C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, orC₁alkyl. In some embodiments, R^(a) is —CH₃.

In some aspects, R^(b), R^(b1), R^(b2), R^(b3), and R^(b4) in Formula IIare independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein saidC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy.

In some aspects, R^(c) and R^(d) in Formula II are independently H,C₁-C₁₀ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁-C₁₀ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy, orheterocycloalkyl group.

In some embodiments, R^(c) and R^(d) in Formula II, together with the Natom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, CN, amino,halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy.

In some aspects, R^(c1) and R^(d1) in Formula II are independently H,C₁-C₁₀ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁-C₁₀ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy.

In some embodiments, R^(c1) and R^(d1) in Formula II, together with theN atom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, CN, amino,halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy.

In some aspects, R^(c2) and R^(d2) in Formula II are independently H,C₁-C₁₀ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroaryl aryl, or biheteroaryl, whereinsaid C₁-C₁₀ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroaryl aryl, and biheteroaryl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,C(O)OR^(a4), C(O)R^(b4), S(O)₂R^(b3), alkoxyalkyl, and alkoxyalkoxy.

In some aspects, R^(c2) and R^(d2) in Formula II, together with the Natom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, CN, amino,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C(O)OR^(a4), C(O)R^(b4),S(O)₂R^(b3), alkoxyalkyl, and alkoxyalkoxy.

In some aspects, R^(c3) and R^(d3) in Formula II are independently H,C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁-C₁₀ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy.

In some aspects, R^(c3) and R^(d3) in Formula II together with the Natom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, CN, amino,halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy.

In some aspects, R^(c4) and R^(d4) in Formula II are independently H,C₁-C₁₀ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁-C₁₀ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy.

In some aspects, R^(c4) and R^(d4) in Formula II together with the Natom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, CN, amino,halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy.

In some aspects, R^(e1), R^(e2), and R^(e3) in Formula II areindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, (C₁-C₆alkoxy)-C₁-C₆ alkyl, C₂-C₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, orheterocycloalkylalkyl.

In some aspects, R^(f1), R^(f2), and R^(G) in Formula II areindependently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, cycloalkyl, heteroaryl, andheterocycloalkyl.

In some aspects, R^(g1) in Formula II is H, CN, or NO₂.

In some aspects, the disclosure is directed to compounds of Formula IIA:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   Q is —O—, —S—, —S(O)—, or —S(O)₂—;    -   R is halo; n=1;    -   the moiety -W¹-W²-W³ is —CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—,        —O—CR^(2B)R^(2C)—CR²R^(2A)—, —CR²R^(2A)—CR^(2B)R^(2C)—O—,        —S—CR^(2B)R^(2C)—CR²R^(2A), or —CR²R^(2A)—CR^(2B)R^(2C)—S—;    -   R² and R^(2A) are each independently H, halo, or C₁-C₆alkyl, or        R² and R^(2A) that are attached to the same carbon atom may,        together with the carbon atom to which they are both attached,        form a C₃-C₆cycloalkyl ring;    -   R^(2B) and R^(2C) are each independently H or C₁-C₆alkyl, or        R^(2B) and R^(2C) may, together with the carbon atom to which        they are both attached, form a C₃-C₆cycloalkyl ring;    -   R³ is H or C₁-C₆alkyl;    -   L¹ is —C₁-C₆alkylene-;    -   L² is C₃-C₇ cycloalkylene, C₄-C₇ heterocycloalkylene or        heteroarylene;    -   L³ is absent, or is —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—,        —NR^(6A)S(O)₂—, —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —NR^(6A)C(O),        —C(═O)NR^(6A)—;    -   L⁴ is absent, —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—, or        —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —CR^(4A)═CR^(4B)—, or        —O—, —S—, —S(O)—, —S(O)₂—, —NR⁶—, —NR^(6A)C(O), or        —C(═O)NR^(6A)—;    -   L⁵ is absent, or is a 6-10 membered arylene or 5-10 membered        heteroarylene, wherein said heteroarylene is optionally        substituted with C₁-C₆ alkyl, OC₂-C₆ alkyl NR^(c3)R^(d3), or        —C₁-C₆ alkyl-C(O)NR^(c3)R^(d3);    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—;    -   p=0-4; q=0-3; s=1;    -   each R⁴ is independently H, OH, —C₁-C₆alkyl, or —OC₁-C₆alkyl,    -   each R⁵ is independently selected from is H, OH, —C₁-C₆alkyl, or        —OC₁-C₆alkyl;    -   each R⁶ is independently selected from is H or —C₁-C₆alkyl;    -   each R^(6A) is independently selected from H, or C₁-C₆alkyl;    -   each R⁷ is H, —C₁-C₆alkyl, or —OC₁-C₆alkyl;    -   each R^(4A) and R^(4B) is independently H, Me, CF₃ or F; and    -   each R⁸ is H, —C₁-C₆alkyl, or —OC₁-C₆alkyl;    -   R^(c3) and R^(d3) together with the N atom to which they are        attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group        optionally substituted with 1, 2, or 3 substituents        independently selected from OH, C₁-C₆alkyl, C₁-C₆alkoxy, or        C₁-C₆alk-C₁-C₆ alkoxy.

In some aspects, the disclosure is directed to compounds of FormulaIIA-1:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   L² is C₄ cycloalkylene, C₅ heterocycloalkylene or heteroarylene;    -   L³ is absent, or is —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—,        —NR^(6A)S(O)₂—, —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —NR^(6A)C(O),        —C(═O)NR^(6A)—;    -   L⁴ is absent, —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—, or        —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —CR^(4A)═CR^(4B)—, or        —O—, —S—, —S(O)—, —S(O)₂—, —NR⁶—, —NR^(6A)C(O), or        —C(═O)NR^(6A)—;    -   L⁵ is absent, a 6-membered arylene, or a 5- or 6-membered        heteroarylene, wherein said heteroarylene is optionally        substituted with —C₁-C₆ alkyl, OC₂₋₆ alkyl NR^(c3)R^(d3), or        —C₁-C₆ alkyl-C(O)NR^(c3)R^(d3);    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—;    -   p=0-4; and q=0-3; s=1;    -   each R⁴ is independently selected from H, OH, —C₁-C₆alkyl, and        —OC₁-C₆alkyl,    -   each R⁵ is independently selected from H, OH, —C₁-C₆alkyl, and        —OC₁-C₆alkyl;    -   each R⁶ is independently selected from H and —C₁-C₆alkyl;    -   each R^(6A) is independently selected from H, and C₁-C₆alkyl;    -   each R⁷ is H, —C₁-C₆alkyl, or —OC₁-C₆alkyl;    -   each R^(4A) and R^(4B) is independently H, Me, CF₃ or F; and    -   each R⁸ is H, —C₁-C₆alkyl, or —OC₁-C₆alkyl; R^(c3) and R^(d3)        together with the N atom to which they are attached form a 4-,        5-, 6- or 7-membered heterocycloalkyl group optionally        substituted with 1, 2, or 3 substituents independently selected        from OH, C₁-C₆alkyl, C₁-C₆alkoxy, or C₁-C₆alk-C₁-C₆ alkoxy.

In some embodiments, the compounds of Formula IIA-1 are those wherein L²is heteroarylene, L³ is absent, L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—,wherein Q¹ is —CR^(4A)═CR^(4B)—; L⁵ is absent, L⁶ is absent, p=1; andq=3, R⁴ and R⁵ are H; R^(4A) and R^(4B) are H.

In some aspects, the disclosure is directed to compounds of FormulaIIA-2:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   L³ is absent, or is —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—,        —NR^(6A)S(O)₂—, —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —NR^(6A)C(O),        —C(═O)NR^(6A)—;    -   L⁴ is absent, —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—, or        —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —CR^(4A)═CR^(4B)—, or        —O—, —S—, —S(O)—, —S(O)₂—, —NR⁶—, —NR^(6A)C(O), or        —C(═O)NR^(6A)—;    -   L⁵ is 6-membered arylene or 5- or 6-membered heteroaryl ene,        wherein said heteroarylene is optionally substituted with —C₁-C₆        alkyl, —OC₂-C₆alkyl NR^(c3)R^(d3), or —C₁-C₆        alkyl-C(O)NR^(c3)R^(d3);    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—;    -   p=0-4; q=0-3; and s=1;    -   each R⁴ is independently H, OH, or —OC₁-C₆alkyl;    -   each R⁵ is independently selected from is H, OH, or        —OC₁-C₆alkyl;    -   each R⁶ is independently selected from is H or —C₁-C₆alkyl;    -   each R^(6A) is independently selected from H or C₁alkyl;    -   each R⁷ is H, —C₁alkyl, or —OC₁alkyl;    -   each R^(4A) and R^(4B) is H;    -   each R⁸ is H, —C₁alkyl, or —OC₁alkyl; R^(c3) and R^(d3) together        with the N atom to which they are attached form a 6-membered        heterocycloalkyl group optionally substituted with —C₁-C₆ alkoxy        or —C₁-C₆ alk-C₁-C₆ alkoxy.

In some aspects, the disclosure is directed to compounds of FormulaIIA-3:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   L³ is absent, or is —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—,        —NR^(6A)S(O)₂—, —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —NR^(6A)C(O),        —C(═O)NR^(6A)—;    -   L⁴ is absent, —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—, or        —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —CR^(4A)═CR^(4B)—, or        —O—, —S—, —S(O)—, —S(O)₂—, —NR⁶—, —NR^(6A)C(O), or        —C(═O)NR^(6A)—;    -   L⁵ is phenyl;    -   L⁶ is —(CR⁷R⁸)_(s)—;    -   p=0-4; q=0-3; and s=1    -   each R⁴ is independently H, OH, or —OC₁-C₆alkyl;    -   each R⁵ is independently selected from is H, OH, or        —OC₁-C₆alkyl;    -   each R⁶ is independently selected from is H or —C₁-C₆alkyl;    -   each R^(6A) is independently selected from H or C₁alkyl;    -   each R⁷ is H, —C₁alkyl, or —OC₁alkyl;    -   each R^(4A) and R^(4B) is H;    -   each R⁸ is H, —C₁alkyl, or —OC₁alkyl.

In some embodiments, the compounds of Formula IIA-3 are those wherein

L³ is absent,

L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —O— or —S—,

L⁵ is phenyl;

L⁶ is —(CR⁷R⁸)_(s)—;

p=1-2; q=0-1; and s=1-2;

each R⁴ is independently H, OH, or —OC₁-C₆alkyl;

each R⁵ is independently selected from is H, OH, or —OC₁-C₆alkyl;

each R⁷ is H, —C₁alkyl, or —OC₁alkyl; and

each R⁸ is H, —C₁alkyl, or —OC₁alkyl.

In other embodiments, the compounds of Formula IIA-3 are those wherein

L³ is absent;

L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —O— or —S—;

L⁵ is phenyl;

L⁶ is —(CR⁷R⁸)_(s)—;

p=1; q=0; and s=1

each R⁴ is independently H, OH, or —OC₁-C₆alkyl;

each R⁵ is independently selected from is H, OH, or —OC₁-C₆alkyl;

each R⁷ is H, —C₁alkyl, or —OC₁alkyl; and

each R⁸ is H, —C₁alkyl, or —OC₁alkyl.

In other embodiments, the compounds of Formula IIA-3 are those whereinL³ is absent; L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —O— or—S—; L⁵ is phenyl; L⁶ is —(CR⁷R⁸)_(s)—; p=1; q=0; and s=1; each R⁴ is H;each R⁵ is H; R⁷ is H; and R⁸ is H.

In some aspects, the disclosure is directed to compounds of Formula IIB:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   Q is —O—, —S—, —S(O)—, or —S(O)₂—;    -   the moiety -W¹-W²-W³ is —CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—,        —O—CR^(2B)R^(2C)—CR²R^(2A)—, —CR²R^(2A)—CR^(2B)R^(2C)—O—,        —S—CR^(2B)R^(2C)—CR²R^(2A), or —CR²R^(2A)—CR^(2B)R^(2C)—S—;    -   R² and R^(2A) are each independently H, halo, C₁-C₆alkyl, or R²        and R^(2A) that are attached to the same carbon atom may,        together with the carbon atom to which they are both attached,        form a C₃-C₆cycloalkyl ring;    -   R^(2B) and R^(2C) are each independently H or C₁-C₆alkyl, or        R^(2B) and R^(2C) may, together with the carbon atom to which        they are both attached, form a C₃-C₆cycloalkyl ring;    -   R is halo, —S—C₁-C₆alkyl, or —O—C₁-C₆alkyl; n=1 or 2;    -   R¹ is halo, —CH₂—CN, —C₁-C₆haloalkyl, —OC₁-C₆haloalkyl,        —OC₁-C₆haloalkyl, —C₁-C₆alk-OH, —C₁-C₆alk-O—C₁-C₆alkyl,        —O—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O—C₃-C₆cycloalkyl,        —C₁-C₆alk-O—C₁-C₆haloalkyl, or

-   -   -   m=1 or 2

    -   L³ is absent, or is —NR⁶S(O)—, —S(═O)₂NR⁶—, —NR⁶S(O)₂—,

    -   L⁴ is —(CR⁴R⁵)_(p), (CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)O(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)—S(═O)₂NR^(6A)—(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)S(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)S(O)(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)S(O)₂(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)C(O)NR^(6A)(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)NR^(6A)C(O)(CR⁴R⁵)_(q), or        —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—;

    -   wherein each occurrence of p or q is independently p=0-2 and        q=1-5;

    -   L⁵ is absent,

    -   L⁶ is absent, or is (CR⁷R⁸)_(s)O(CR⁷R⁸)_(t),        (CR⁷R⁸)_(s)NR⁹(CR⁷R⁸>, (CR⁷R⁸)_(s)S(CR⁷R⁸)_(t),        (CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t), or (CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t);

    -   wherein each occurrence of s or t is independently s=0-2 and        t=0-2;

    -   each R⁴ and each R⁷ is independently selected from H, OH,        C₁-C₆alkyl, C₁-C₆haloalkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl,        —OC₃-C₇cycloalkyl, —CH₂—CN, —CN, —N(CH₃)₂,

-   -   each R⁵ and each R⁸ is independently selected from H, OH,        —CH₂OH, C₁-C₆alkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl, and        —OC₃-C₇cycloalkyl;    -   wherein one R⁴ and R⁵ together with the C atom to which they are        both attached may optionally form a 3, 4, 5, or 6-membered        cycloalkyl ring,

and

-   -   each R⁹ is independently H or —C₁-C₆alkyl.    -   and each R^(4A) and each R^(4B) is independently selected from        H, Me, CF₃, and F.

In some aspects, the disclosure is directed to compounds of FormulaIIB-1:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   the moiety -W¹-W²-W³ is —CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—,        —O—CR^(2B)R^(2C)—CR²R^(2A)—, —CR²R^(2A)—CR^(2B)R^(2C)—O—,        —S—CR^(2B)R^(2C)—CR²R^(2A), or —CR²R^(2A)—CR^(2B)R^(2C)—S—;    -   R² and R^(2A) are each independently H, halo, C₁-C₆alkyl, or R²        and R^(2A) that are attached to the same carbon atom may,        together with the carbon atom to which they are both attached,        form a C₃-C₆spirocycloalkyl ring;    -   R^(2B) and R^(2C) are each independently H or C₁-C₆alkyl, or        R^(2B) and R^(2C) may, together with the carbon atom to which        they are both attached, form a C₃-C₆spirocycloalkyl ring;    -   R is halo, —S—C₁-C₆alkyl, or —O—C₁-C₆alkyl; n=1 or 2;    -   R¹ is halo, —CH₂—CN, —C₁-C₆haloalkyl, —OC₁-C₆haloalkyl,        —OC₁-C₆haloalkyl, —C₁-C₆alk-OH, —C₁-C₆alk-O—C₁-C₆alkyl,        —O—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O—C₃-C₆cycloalkyl,        —C₁-C₆alk-O—C₁-C₆haloalkyl, or

-   -   -   m=1 or 2

    -   L³ is absent, or is —NR⁶S(O)—, —S(═O)₂NR⁶—, —NR⁶S(O)₂—,

    -   L⁴ is —(CR⁴R⁵)_(p), (CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)O(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)—S(═O)₂NR^(6A)—(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)S(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)S(O)(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)S(O)₂(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)C(O)NR^(6A)(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)NR^(6A)C(O)(CR⁴R⁵)_(q), or        —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—;

    -   wherein each occurrence of p or q is independently p=0-2 and        q=1-5;

    -   L⁵ is absent,

    -   L⁶ is absent, or is (CR⁷R⁸)_(s)O(CR⁷R⁸)_(t),        (CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)S(CR⁷R⁸)_(t),        (CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t), or (CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t);

    -   wherein each occurrence of s or t is independently s=0-2 and        t=0-2;

    -   each R⁴ and each R⁷ is independently selected from H, OH,        C₁-C₆alkyl, C₁-C₆haloalkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl,        —OC₃-C₇cycloalkyl, —CH₂—CN, —CN, —N(CH₃)₂,

-   -   each R⁵ and each R⁸ is independently selected from H, OH,        —CH₂OH, C₁-C₆alkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl, and        —OC₃-C₇cycloalkyl;    -   wherein one R⁴ and R⁵ together with the C atom to which they are        both attached may optionally form a 3, 4, 5, or 6-membered        cycloalkyl ring,

and

-   -   each R⁹ is independently H or —C₁-C₆alkyl.    -   and each R^(4A) and each R^(4B) is independently selected from        H, Me, CF₃, or F.

In some aspects, the disclosure is directed to compounds of FormulaIIB-2:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   R is halo, —S—C₁-C₆alkyl, or —O—C₁-C₆alkyl; n=1 or 2;    -   R¹ is halo, —CH₂—CN, —C₁-C₆haloalkyl, —OC₁-C₆haloalkyl,        —OC₁-C₆haloalkyl, —C₁-C₆alk-OH, —C₁-C₆alk-O—C₁-C₆alkyl,        —O—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O—C₃-C₆cycloalkyl,        —C₁-C₆alk-O—C₁-C₆haloalkyl, or

-   -   -   m=1 or 2

    -   L³ is absent, or is —NR⁶S(O)—, —S(═O)₂NR⁶—, —NR⁶S(O)₂—,

    -   L⁴ is —(CR⁴R⁵)_(p), (CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)O(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)—S(═O)₂NR^(6A)—(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)S(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)S(O)(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)S(O)₂(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)C(O)NR^(6A)(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)NR^(6A)C(O)(CR⁴R⁵)_(q), or        —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—;

    -   wherein each occurrence of p or q is independently p=0-2 and        q=1-5;

    -   L⁵ is absent,

    -   L⁶ is absent, or is (CR⁷R⁸)_(s)O(CR⁷R⁸)_(t),        (CR⁷R⁸)_(s)NR⁹(CR⁷R⁸>, (CR⁷R⁸)_(s)S(CR⁷R⁸)_(t),        (CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t), or (CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t);

    -   wherein each occurrence of s or t is independently s=0-2 and        t=0-2;

    -   each R⁴ and each R⁷ is independently selected from H, OH,        C₁-C₆alkyl, C₁-C₆haloalkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl,        —OC₃-C₇cycloalkyl, —CH₂—CN, —CN, —N(CH₃)₂,

-   -   each R⁵ and each R⁸ is independently selected from H, OH,        —CH₂OH, C₁-C₆alkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl,        —OC₃-C₇cycloalkyl;    -   wherein one R⁴ and R⁵ together with the C atom to which they are        both attached may optionally form a 3, 4, 5, or 6-membered        cycloalkyl ring,

and

-   -   each R⁹ is independently H or —C₁-C₆alkyl.    -   and each R^(4A) and each R^(4B) is independently selected from        H, Me, CF₃, or F.

In some aspects, the disclosure is directed to compounds of FormulaIIB-3:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   L³ is absent, or is —NR⁶S(O)—, —S(═O)₂NR⁶—, —NR⁶S(O)₂—, L⁴ is        —(CR⁴R⁵)_(p), (CR⁴R⁵)_(p)—CR^(4B)═CR^(4B)—(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)O(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)—S(═O)₂NR^(6A)—(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)S(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)S(O)(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)S(O)₂(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)C(O)NR^(6A)(CR⁴R⁵)_(q),        (CR⁴R⁵)_(p)NR^(6A)C(O)(CR⁴R⁵)_(q), or        —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—;    -   wherein each occurrence of p or q is independently p=0-2 and        q=1-5;    -   L⁵ is absent,    -   L⁶ is absent, or is (CR⁷R⁸)_(s)O(CR⁷R⁸)_(t),        (CR⁷R⁸)_(s)NR⁹(CR⁷R⁸>, (CR⁷R⁸)_(s)S(CR⁷R⁸)_(t),        (CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t), or (CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t);    -   wherein each occurrence of s or t is independently s=0-2 and        t=0-2;    -   each R⁴ and each R⁷ is independently selected from H, OH,        C₁-C₆alkyl, C₁-C₆haloalkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl, and        —OC₃-C₇cycloalkyl;    -   each R⁵ and each R⁸ is independently selected from H, OH,        —CH₂OH, C₁-C₆alkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl, and        —OC₃-C₇cycloalkyl;    -   wherein one R⁴ and R⁵ together with the C atom to which they are        both attached may form a 3, 4, 5, or 6-membered cycloalkyl ring;        and    -   each R^(4A) and each R^(4B) is independently selected from H,        Me, CF₃ and F; and    -   each R⁹ is independently H or —C₁-C₆alkyl.

In some aspects, the disclosure is directed to compounds of FormulaIIB-4:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   L⁴ is —(CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q)—;    -   p=1 and q=1-4.    -   each R⁴ is independently selected from H, OH, C₁-C₆alkyl,        C₁-C₆haloalkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl,        —OC₃-C₇cycloalkyl, —CH₂—CN, —CN, —N(CH₃)₂,

-   -   each R⁵ is independently selected from H, OH, —CH₂OH,        C₁-C₆alkyl, —OC₁-C₆alkyl, —C₃-C₇cycloalkyl, and        —OC₃-C₇cycloalkyl;    -   and each R^(4A) and each R^(4B) is independently selected from        H, Me, and F.

In some aspects, the disclosure is directed to compounds of FormulaIIB-5:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   L⁴ is —(CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q)—;    -   p=1 and q=1-4;    -   R⁴ is independently H, or —C₁-C₆alkyl;    -   R⁵ is independently H, or C₁-C₆alkyl;    -   wherein one R⁴ and one R⁵, together with the carbon atom to        which they are both attached, are

-   -   and each R^(4A) and each R^(4B) is independently selected from        H, Me, or F.

In some aspects, the disclosure is directed to compounds of FormulaIIB-6:

or a pharmaceutically acceptable salt or solvate thereof;

whereinR¹ is halo, —CH₂—CN, —C₁-C₆haloalkyl, —OC₁-C₆haloalkyl,—OC₁-C₆haloalkyl, —C₁-C₆alk-OH, —C₁-C₆alk-O—C₁-C₆alkyl,—O—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O—C₃-C₆cycloalkyl,—C₁-C₆alk-O—C₁-C₆haloalkyl, or

m=1 or 2;L⁴ is —(CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q)—;

p=1 and q=1-4;

R⁴ is independently H, —OC₁-C₆alkyl, or —C₁-C₆alkyl;R⁵ is independently H, —OC₁-C₆alkyl, or —C₁-C₆alkyl;R^(4A) and R^(4B) are H.

In some aspects, the disclosure is directed to compounds of FormulaIIB-7:

or a pharmaceutically acceptable salt or solvate thereof;

whereinR is halo, —S—C₁-C₆alkyl, or —O—C₁-C₆alkyl;n=1 or 2;L⁴ is —(CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q)—;

p=1 and q=1-4;

R⁴ is independently H, —OC₁-C₆alkyl, or —C₁-C₆alkyl;R⁵ is independently H, —OC₁-C₆alkyl, or —C₁-C₆alkyl;R^(4A) and R^(4B) are H.

The disclosure is directed to compounds of Formula IIC:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   Q is —O—, or —S—;    -   R is halo; n=1;    -   the moiety -W¹-W²-W³ is —CH₂—CH₂—CH₂—, —O—CH₂—CH₂—, or        —CH₂—CH₂—O—;    -   R³ is H, or C₁-C₆alkyl;    -   L¹ is —C₁-C₆alkylene-;    -   L² is C₃-C₇cycloalkyl, or C₄-C₇heterocycloalkylene;    -   L³ is absent, or is —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —S(O)₂—,        —C(═O)—, —NR⁶—;    -   L⁴ is absent or is —(CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q),        —(CR⁴R⁵)_(p)O(CR⁴R⁵)_(q)—;    -   L⁵ is a 6-membered arylene, 5-membered heteroarylene, 7-to        10-membered spirocycloalkylene, 7- to        10-spiroheterocycloalkylene, 3- to 7-membered monocyclic        cycloalkylene, 3- to 7-membered cycloalkenylene, or a 4- to        7-membered monocyclic heterocycloalkylene group, wherein the        spiroheterocycloalkylene or heterocycloalkylene groups have 1,        2, 3 or 4, heteroatoms independently selected from O, or N;    -   L⁶ is absent, or is —(CR⁷R⁸)_(s), (CR⁷R⁸)_(s)O(CR⁷R⁸>,        —(CR⁷R⁸)_(a)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(c),        (CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t); —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—, or        —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—;    -   each R⁴ is independently H, OH, or —OC₁-C₆alkyl;    -   each R⁵ is independently selected from is H, OH, or        —OC₁-C₆alkyl;        -   or R⁴ and R⁵ together with the C atom to which they are both            attached may form a 3, 4, 5, 6, or 7-membered cycloalkyl            ring;    -   each R⁶ is independently selected from is H or —C₁-C₆alkyl,    -   each R⁷ is H, OH, —C₁-C₆alkyl, or —OC₁-C₆alkyl,    -   each R⁸ is H, OH, —C₁-C₆alkyl, or —OC₁-C₆alkyl;        -   or R⁷ and R⁸ together with the C atom to which they are both            attached may form a 3, 4, 5, 6, or 7-membered cycloalkyl            ring;    -   each R^(4A) and each R^(4B) is independently H, or —OC₁-C₆alkyl;    -   a=0-1; c=0-3; p=0-3; s=0-2, t=0-5; and q=0-2;

In some aspects, the disclosure is directed to compounds of FormulaIIC-1:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   L² is C₃-C₆cycloalkylene, or heterocycloalkylene;    -   L³ is absent, or is —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —S(O)₂—,        —C(═O)—, —NR⁶—;    -   L⁴ is absent or is —(CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q),        —(CR⁴R⁵)_(p)O(CR⁴R⁵)_(q)—;    -   L⁵ is a 6-membered arylene, or 5-membered heteroarylene, 7- to        10-membered spirocycloalkylene, 7- to        10-spiroheterocycloalkylene, 3- to 7-membered cycloalkylene, 3-        to 7-membered cycloalkenylene, or a 4- to 7-membered        heterocycloalkylene group, wherein the spiroheterocycloalkylene        or heterocycloalkylene groups have 1, 2, 3 or 4, heteroatoms        independently selected from O, or N;    -   L⁶ is absent, —(CR⁷R⁸)_(s), (CR⁷R⁸)_(s)O(CR⁷R⁸)_(t),        —(CR⁷R⁸)_(a)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(c),        (CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t); —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—, or        —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—;    -   a=0-1; c=0-3; p=0-3; s=0-2, t=0-5; and q=0-2;    -   each R⁴ is independently H, OH, or —OC₁-C₆alkyl;    -   each R⁵ is independently selected from is H, OH, or        —OC₁-C₆alkyl;    -   or R⁴ and R⁵ together with the C atom to which they are both        attached may form a 3, 4, 5, 6, or 7-membered cycloalkyl ring;    -   each R^(4A) and each R^(4B) is independently H, or —OC₁-C₆alkyl;    -   each R⁶ is independently selected from is H or —C₁-C₆alkyl;    -   each R⁷ is H, OH, —C₁-C₆alkyl, or —OC₁-C₆alkyl;    -   each R⁸ is H, OH, —C₁-C₆alkyl, or —OC₁-C₆alkyl;    -   or R⁷ and R⁸ together with the C atom to which they are both        attached may form a 3, 4, 5, 6, or 7-membered cycloalkyl ring.

In some aspects, the disclosure is directed to compounds of FormulaIIC-2:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   L³ is absent, or is —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —S(O)₂—,        —C(═O)—, —NR⁶—;    -   L⁴ is absent or is —(CR⁴R⁵)_(p)—CR^(4A)═CR^(4B)—(CR⁴R⁵)_(q),        —(CR⁴R⁵)_(p)O(CR⁴R⁵)_(q)—,    -   L⁵ is a 7- to 10-membered spirocycloalkylene, 7- to        10-spiroheterocycloalkylene, 3- to 7-membered cycloalkylene, 3-        to 7-membered cycloalkenylene, or a 4- to 7-membered        heterocycloalkylene group, wherein the spiroheterocycloalkylene        or heterocycloalkylene groups have 1, 2, 3 or 4, heteroatoms        independently selected from O, or N;    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—, (CR⁷R⁸)_(s)O(CR⁷R⁸)_(t), or        (CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t); a=0-1; c=0-3; n=1; p=0-1; s=0-2;        t=0-2; and q=0-2;    -   each R⁴ is independently H, OH, or —OC₁-C₆alkyl;    -   each R^(4A) and each R^(4B) is independently H, or —OC₁-C₆alkyl;    -   each R⁵ is independently selected from is H, OH, or        —OC₁-C₆alkyl;    -   each R⁶ is independently selected from is H or —C₁-C₆alkyl,    -   each R⁷ is independently H, —C₁-C₆alkyl, or —OC₁-C₆alkyl; and    -   each R⁸ is independently H, —C₁-C₆alkyl, or —OC₁-C₆alkyl.

In some aspects, the disclosure is directed to compounds of FormulaIIC-3:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   L⁶ is —(CR⁷R⁸)_(a)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(c),        (CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t); —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—, or        —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—; a=0-1; c=1-3; n=1; s=0-2,        t=0-5;    -   each R⁴ is independently H, OH, or —OC₁-C₆alkyl;    -   each R^(4A) and each R^(4B) is H;    -   each R⁵ is independently selected from is H, OH, or        —OC₁-C₆alkyl;    -   each R⁶ is independently selected from is H or —C₁-C₆alkyl,    -   each R⁷ is independently H, —C₁-C₆alkyl, or —OC₁-C₆alkyl,    -   each R⁸ is independently H, —C₁-C₆alkyl, or —OC₁-C₆alkyl;    -   or R⁷ and R⁸, together with the carbon atom to which they are        attached, for a C₃-C₆ cycloalyl ring.

It will be apparent that the compounds of Formula I and Formula II,including all subgenera described herein, have multiple stereogeniccenters. As a result, there exist multiple stereoisomers (enantiomersand diastereomers) of the compounds of Formula I and Formula II(subgenera described herein). The present disclosure contemplates andencompasses each stereoisomer of any compound of Formula I and FormulaII (and subgenera described herein), as well as mixtures of saidstereoisomers.

Pharmaceutically acceptable salts and solvates of the compounds ofFormula I and Formula II (including all subgenera described herein) arealso within the scope of the disclosure.

Isotopic variants of the compounds of Formula I and Formula II(including all subgenera described herein) are also contemplated by thepresent disclosure.

Pharmaceutical Compositions and Methods of Administration

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentdisclosure as the active ingredient, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof. Wheredesired, the pharmaceutical compositions contain pharmaceuticallyacceptable salt and/or coordination complex thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,the one or more compounds of the invention and other agent(s) may bemixed into a preparation or both components may be formulated intoseparate preparations to use them in combination separately or at thesame time.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is less than100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%,0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%,0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%,0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%,0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number inthe range defined by and including any two numbers above) w/w, w/v orv/v.

In some embodiments, the concentration of one or more compounds of theinvention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%,12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%,7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%,4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%,1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%,0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%,0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%,0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or0.0001% (or a number in the range defined by and including any twonumbers above) w/w, w/v, or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.001% to approximately10%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds of theinvention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g,2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g,0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in therange defined by and including any two numbers above).

In some embodiments, the amount of one or more compounds of theinvention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range definedby and including any two numbers above).

In some embodiments, the amount of one or more compounds of theinvention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, andfrom 5 to 40 mg per day are examples of dosages that may be used. Anexemplary dosage is 10 to 30 mg per day. The exact dosage will dependupon the route of administration, the form in which the compound isadministered, the subject to be treated, the body weight of the subjectto be treated, and the preference and experience of the attendingphysician.

A pharmaceutical composition of the invention typically contains anactive ingredient (i.e., a compound of the disclosure) of the presentinvention or a pharmaceutically acceptable salt and/or coordinationcomplex thereof, and one or more pharmaceutically acceptable excipients,carriers, including but not limited to inert solid diluents and fillers,diluents, sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers and adjuvants.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

Pharmaceutical Compositions for Oral Administration.

In some embodiments, the invention provides a pharmaceutical compositionfor oral administration containing a compound of the invention, and apharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof a compound of the invention; optionally (ii) an effective amount of asecond agent; and (iii) a pharmaceutical excipient suitable for oraladministration. In some embodiments, the composition further contains:(iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, cachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such dosage forms can beprepared by any of the methods of pharmacy, but all methods include thestep of bringing the active ingredient into association with thecarrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising an active ingredient, since water canfacilitate the degradation of some compounds. For example, water may beadded (e.g., 5%) in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time. Anhydrouspharmaceutical compositions and dosage forms of the invention can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. Pharmaceutical compositions anddosage forms of the invention which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition may be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions maybe packaged using materials known to prevent exposure to water such thatthey can be included in suitable formulary kits. Examples of suitablepackaging include, but are not limited to, hermetically sealed foils,plastic or the like, unit dose containers, blister packs, and strippacks.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the compositions for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) maybe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used may vary based upon the type of formulationand mode of administration, and may be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, maybe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms of theinvention include, but are not limited to, agar-agar, alginic acid,calcium carbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein may be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, ifso desired, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions.

Hydrophilic surfactants are generally considered to be those compoundshaving an HLB value greater than about 10, as well as anionic, cationic,or zwitterionic compounds for which the HLB scale is not generallyapplicable. Similarly, lipophilic (i.e., hydrophobic) surfactants arecompounds having an HLB value equal to or less than about 10. However,HLB value of a surfactant is merely a rough guide generally used toenable formulation of industrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acyl lactylates; mono- and di-acetylatedtartaric acid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP—phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrosemono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use, e.g., compositions for injection. A solubilizer may alsobe added to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, 8-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributyl citrate, acetyl tri ethyl citrate,acetyl tributyl citrate, tri ethyl citrate, ethyl oleate, ethylcaprylate, ethyl butyrate, triacetin, propylene glycol monoacetate,propylene glycol diacetate, ε-caprolactone and isomers thereof,δ-valerolactone and isomers thereof, β-butyrolactone and isomersthereof; and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin,diethylene glycol monoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a subjectusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100% o, or up to about 200%> by weight, based on the combinedweight of the drug, and other excipients. If desired, very small amountsof solubilizer may also be used, such as 5%>, 2%>, 1%) or even less.Typically, the solubilizer may be present in an amount of about 1%> toabout 100%, more typically about 5%> to about 25%> by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, toniciflers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Example may include,but not limited to, sodium, potassium, lithium, magnesium, calcium andammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical Compositions for Injection.

In some embodiments, the invention provides a pharmaceutical compositionfor injection containing a compound of the present invention and apharmaceutical excipient suitable for injection. Components and amountsof agents in the compositions are as described herein.

The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof the present invention in the required amount in the appropriatesolvent with various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions,certain desirable methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Pharmaceutical Compositions for Topical (e.g. Transdermal) Delivery.

In some embodiments, the invention provides a pharmaceutical compositionfor transdermal delivery containing a compound of the present inventionand a pharmaceutical excipient suitable for transdermal delivery.

Compositions of the present invention can be formulated intopreparations in solid, semisolid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation.

Examples of such carriers and excipients include, but are not limitedto, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols(e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g.,isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerolmonolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides,alkanes, alkanols, water, calcium carbonate, calcium phosphate, varioussugars, starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a compound of the present invention in controlled amounts,either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical Compositions for Inhalation.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

Other Pharmaceutical Compositions.

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical compositions are well-known in the art. See, e.g.,Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology,Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., ThePharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams &Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-SecondEdition (The Pharmaceutical Press, London, 1999); all of which areincorporated by reference herein in their entirety.

Administration of the compounds or pharmaceutical composition of thepresent invention can be effected by any method that enables delivery ofthe compounds to the site of action. These methods include oral routes,intraduodenal routes, parenteral injection (including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion), topical (e.g. transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. Compounds can also be administered intraadiposallyor intrathecally.

In some embodiments, the compounds or pharmaceutical composition of thepresent invention are administered by intravenous injection.

The amount of the compound administered will be dependent on the subjectbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose.

Typically, such administration will be by injection, e.g., intravenousinjection, in order to introduce the agent quickly. However, otherroutes may be used as appropriate. A single dose of a compound of theinvention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the compounds of the invention may continue as long asnecessary. In some embodiments, a compound of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, a compound of the invention is administered for less than28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound ofthe invention is administered chronically on an ongoing basis, e.g., forthe treatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. Compounds of the invention may beapplied to the surface of the stent by various methods such as dip/spincoating, spray coating, dip-coating, and/or brush-coating. The compoundsmay be applied in a solvent and the solvent may be allowed to evaporate,thus forming a layer of compound onto the stent. Alternatively, thecompound may be located in the body of the stent or graft, for examplein microchannels or micropores. When implanted, the compound diffusesout of the body of the stent to contact the arterial wall. Such stentsmay be prepared by dipping a stent manufactured to contain suchmicropores or microchannels into a solution of the compound of theinvention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent may be removed via an additionalbrief solvent wash. In yet other embodiments, compounds of the inventionmay be covalently linked to a stent or graft. A covalent linker may beused which degrades in vivo, leading to the release of the compound ofthe invention. Any bio-labile linkage may be used for such a purpose,such as ester, amide or anhydride linkages. Compounds of the inventionmay additionally be administered intravascularly from a balloon usedduring angioplasty. Extravascular administration of the compounds viathe pericard or via advential application of formulations of theinvention may also be performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference: U.S. Pat. Nos. 5,451,233; 5,040,548;5,061,273; 5,496,346; 5,292,331; 5,674,278; 3,657,744; 4,739,762;5,195,984; 5,292,331; U.S. Pat. Nos. 5,674,278; 5,879,382; 6,344,053.

The compounds of the invention may be administered in dosages. It isknown in the art that due to intersubject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of the invention may be found byroutine experimentation in light of the instant disclosure.

When a compound of the invention is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Methods of Use

The method typically comprises administering to a subject atherapeutically effective amount of a compound of the invention. Thetherapeutically effective amount of the subject combination of compoundsmay vary depending upon the intended application (in vitro or in vivo),or the subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction ofproliferation or downregulation of activity of a target protein. Thespecific dose will vary depending on the particular compounds chosen,the dosing regimen to be followed, whether it is administered incombination with other compounds, timing of administration, the tissueto which it is administered, and the physical delivery system in whichit is carried.

As used herein, the term “IC₅₀” refers to the half maximal inhibitoryconcentration of an inhibitor in inhibiting biological or biochemicalfunction. This quantitative measure indicates how much of a particularinhibitor is needed to inhibit a given biological process (or componentof a process, i.e. an enzyme, cell, cell receptor or microorganism) byhalf. In other words, it is the half maximal (50%) inhibitoryconcentration (IC) of a substance (50% IC, or IC50). EC50 refers to theplasma concentration required for obtaining 50%> of a maximum effect invivo.

In some embodiments, the subject methods utilize a MCL-1 inhibitor withan IC50 value of about or less than a predetermined value, asascertained in an in vitro assay. In some embodiments, the MCL-1inhibitor inhibits MCL-1 a with an IC50 value of about 1 nM or less, 2nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less,80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM orless, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less,190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nMor less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less,400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nMor less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less,750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nMor less, 1 μM or less, 1.1 μM or less, 1.2 μM or less, 1.3 μM or less,1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μMor less, 1.9 μM or less, 2 μM or less, 5 μM or less, 10 μM or less, 15μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less,50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or500 μM, or less, (or a number in the range defined by and including anytwo numbers above).

In some embodiments, the MCL-1 inhibitor selectively inhibits MCL-1 awith an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in therange defined by and including any two numbers above) than its IC50value against one, two, or three other MCL-1s.

In some embodiments, the MCL-1 inhibitor selectively inhibits MCL-1 awith an IC50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900nM, 950 nM, 1 μM, 1.1 μM, 1.2 μM, 1.3 μM, 1.4 μM, 1.5 μM, 1.6 μM, 1.7μM, 1.8 μM, 1.9 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 40μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM,or 500 μM (or in the range defined by and including any two numbersabove), and said IC50 value is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15,20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in therange defined by and including any two numbers above) than its IC50value against one, two or three other MCL-1s.

The subject methods are useful for treating a disease conditionassociated with MCL-1. Any disease condition that results directly orindirectly from an abnormal activity or expression level of MCL-1 can bean intended disease condition.

Different disease conditions associated with MCL-1 have been reported.MCL-1 has been implicated, for example, auto-immune diseases,neurodegeneration (such as Parkinson's disease, Alzheimer's disease andischaemia), inflammatory diseases, viral infections and cancer such as,for example, colon cancer, breast cancer, small-cell lung cancer,non-small-cell lung cancer, bladder cancer, ovarian cancer, prostatecancer, chronic lymphoid leukemia, lymphoma, myeloma, acute myeloidleukemia, or pancreatic cancer.

Non-limiting examples of such conditions include but are not limited toAcanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginousmelanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblasticleukemia, Acute lymphocytic leukemia, Acute megakaryoblastic leukemia,Acute monocytic leukemia, Acute myeloblasts leukemia with maturation,Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acutemyelogenous leukemia, Acute promyelocytic leukemia, Adamantinoma,Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoidodontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia,Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-relatedlymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer,Anaplastic large cell lymphoma, Anaplastic thyroid cancer,Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma,Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basalcell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma,Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma,Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer,Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Browntumor, Burkitt's lymphoma, Cancer of Unknown Primary Site, CarcinoidTumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinomaof Unknown Primary Site, Carcinosarcoma, Castleman's Disease, CentralNervous System Embryonal Tumor, Cerebellar Astrocytoma, CerebralAstrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma,Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma,Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronicmyelogenous leukemia, Chronic Myeloproliferative Disorder, Chronicneutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectalcancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease,Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small roundcell tumor, Diffuse large B cell lymphoma, Dysembryoplasticneuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor,Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor,Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma,Epidermoid cancer, Epithelioid sarcoma, Erythroleukemia, Esophagealcancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing FamilySarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, ExtragonadalGerm Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget'sdisease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma,Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer,Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer,Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal CarcinoidTumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor,Germ cell tumor, Germinoma, Gestational choriocarcinoma, GestationalTrophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme,Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma,Granulosa cell tumor, Hairy Cell Leukemia, Head and Neck Cancer, Headand neck cancer, Heart cancer, Hemoglobinopathies such as b-thalassemiaand sickle cell disease (SCD), Hemangioblastoma, Hemangiopericytoma,Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma,Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancersyndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer,Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma,Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocyticleukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskintumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigomaligna melanoma, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma,Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma,Lymphoepithelioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia,Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma,Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, MalignantMesothelioma, Malignant peripheral nerve sheath tumor, Malignantrhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle celllymphoma, Mast cell leukemia, Mastocytosis, Mediastinal germ cell tumor,Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma,Medulloblastoma, Medulloepithelioma, Melanoma, Melanoma, Meningioma,Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic SquamousNeck Cancer with Occult Primary, Metastatic urothelial carcinoma, MixedMullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor,Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiplemyeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplasia Disease,Myelodysplasia Syndromes, Myeloid leukemia, Myeloid sarcoma,Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, NasopharyngealCancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma,Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-HodgkinLymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small CellLung Cancer, Ocular oncology, Oligoastrocytoma, Oligodendroglioma,Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer,Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer,Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor,Ovarian Low Malignant Potential Tumor, Paget's disease of the breast,Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroidcancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer,Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor,Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor ofIntermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitaryadenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonaryblastoma, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primarycentral nervous system lymphoma, Primary effusion lymphoma, PrimaryHepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer,Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxomaperitonei, Rectal Cancer, Renal cell carcinoma, Respiratory TractCarcinoma Involving the NUT Gene onChromosome 15, Retinoblastoma,Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygealteratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceousgland carcinoma, Secondary neoplasm, Seminoma, Serous tumor,Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome,Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor,Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Smallintestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart,Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma,Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma,Supratentorial Primitive Neuroectodermal Tumor, Surfaceepithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblasticleukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia,T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminallymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, ThymicCarcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of RenalPelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethralcancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, VaginalCancer, Verner Morrison syndrome, Verrucous carcinoma, Visual PathwayGlioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor,Wilms' tumor, or any combination thereof.

In some embodiments, said method is for treating a disease selected fromthe group consisting of tumor angiogenesis, chronic inflammatory diseasesuch as rheumatoid arthritis, atherosclerosis, inflammatory boweldisease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes, diabetic retinopathy, retinopathy of prematurity, age-relatedmacular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

In other embodiments, said method is for treating a disease selectedfrom breast cancer, lung cancer, pancreatic cancer, prostate cancer,colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

In other embodiments, said method is for treating a disease selectedfrom leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),myelodysplastic syndrome (MDS) or epidermoid cancer.

Compounds of the disclosure, as well as pharmaceutical compositionscomprising them, can be administered to treat any of the describeddiseases, alone or in combination with a medical therapy. Medicaltherapies include, for example, surgery and radiotherapy (e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, systemic radioactive isotopes).

In other aspects, compounds of the disclosure, as well as pharmaceuticalcompositions comprising them, can be administered to treat any of thedescribed diseases, alone or in combination with one or more otheragents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with agonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with antagonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with an anti-proliferative agent.

Combination Therapies

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. The compounds of the invention can also beused in combination with a medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenictrioxide, asparaginase, azacitidine, bendamustine, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, mechlorethamine, megestrol acetate, melphalan,mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinibmaleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, vorinstat and zoledronate.

In some embodiments, the compounds of the invention can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferase inhibitors, histonearginine methyl transferase inhibitors, histone demethylase inhibitors,histone deacetylase inhibitors, histone acetylase inhibitors, and DNAmethyltransferase inhibitors. Histone deacetylase inhibitors include,e.g., vorinostat. Histone arginine methyl transferase inhibitors includeinhibitors of protein arginine methyltransferases (PRMTs) such as PRMT5,PRMT1 and PRMT4. DNA methyltransferase inhibitors include inhibitors ofDNMT1 and DNMT3.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with targeted therapies,including JAK kinase inhibitors (e.g. Ruxolitinib), PI3 kinaseinhibitors including PI3K-delta selective and broad spectrum PI3Kinhibitors, MEK inhibitors, Cyclin Dependent kinase inhibitors,including CDK4/6 inhibitors and CDK9 inhibitors, BRAF inhibitors, mTORinhibitors, proteasome inhibitors (e.g. Bortezomib, Carfilzomib), HDACinhibitors (e.g. panobinostat, vorinostat), DNA methyl transferaseinhibitors, dexamethasone, bromo and extra terminal family member (BET)inhibitors, BTK inhibitors (e.g. ibrutinib, acalabrutinib), BCL2inhibitors (e.g. venetoclax), dual BCL2 family inhibitors (e.g.BCL2/BCLxL), PARP inhibitors, FLT3 inhibitors, or LSD 1 inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), or PDR001. In some embodiments,the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD1 antibody is pembrolizumab. In someembodiments, the inhibitor of an immune checkpoint molecule is aninhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is atezolizumab,durvalumab, or BMS-935559. In some embodiments, the inhibitor of animmune checkpoint molecule is an inhibitor of CTLA-4, e.g., ananti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody isipilimumab.

In some embodiments, the agent is an alkylating agent, a proteasomeinhibitor, a corticosteroid, or an immunomodulatory agent. Examples ofan alkylating agent include cyclophosphamide (CY), melphalan (MEL), andbendamustine. In some embodiments, the proteasome inhibitor iscarfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with an immune suppressantsuch as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol,Alcon), or cyclosporine (Restasis®).

Compounds of the disclosure also include, for example, the compounds andgenera identified m Tables A, B, and C.

TABLE A

R = H or C₁-C₆alkyl

n = 1, 2, 3 or 4

R = H or C₁-C₆alkyl

n = 1-3

n = 1-3

TABLE B

n = 0, 1 or 2

X = H, Me, F

X = CHR, O, S, S(O)₂, NR

R = H or C₁-C₆alkyl

R = H or C₁-C₆alkyl

X = OH, F, OMe, OCF₃

R = alkyl, cyclic alkyl, heterocyclic alkyl

R = alkyl, cyclic alkyl, heterocyclic alkyl

R = alkyl, cyclic alkyl, heterocyclic alkyl

R = H or C₁-C₆alkyl

n = 1, 2, 3

R = H or C₁-C₆alkyl

R = H or C₁-C₆alkyl

R = H or C₁-C₆alkyl n = 0-3

TABLE C

R = H or C₁-C₆alkyl

X = CH₂, O, NR

X = CH₂, O, NR

Compounds of the disclosure also include, for example, the compoundsdescribed as Examples below.

Synthesis

Compounds of the invention can be prepared according to numerouspreparatory routes known in the literature. The Schemes below providegeneral guidance in connection with preparing the compounds of theinvention. One skilled in the art would understand that the preparationsshown in the Schemes can be modified or optimized using generalknowledge of organic chemistry to prepare various compounds of theinvention. Example synthetic methods for preparing compounds of theinvention are provided in the Schemes below.

A series of 1,3-diol derivatives of formula 4 (n=0, 1, 2) can beprepared by the methods outlined in Scheme 1. Johnson-Corey-Chaykovskyreaction of the substituted ketone 1 with sulfur ylide can form thecorresponding epoxide 2 which can be converted to the aldehyde 3 underLewis acid (e.g., boron trifluoride diethyl etherate or TiCl₄). Thealdehyde 3 can be transformed to the 1,3-diol derivative 4 by treatmentwith formaldehyde under basic conditions (e.g., KOH).

A series of 1,3-diol derivatives of formula 12 (n=0, 1, 2) can beprepared by the methods outlined in Scheme 2. Compound 7 can be obtainedby protecting the alcohol group (e.g., TBS or other silyl group) in 6obtained from the reduction of the acid 5 using a suitable reductivereagent including, (e.g., BH₃, NaBH₄, LiBH₄, LiAlH₄). Lithiation ofcompound 7 with a suitable agent (e.g., BuLi or another lithium reagent)at low temperature and subsequent reaction of the intermediate with theketone 8 can afford the alcohol derivative 9. Removal of the protectinggroup (e.g., TBAF removal of TBS group) followed by intra-molecularMitsunobo reaction (e.g., DEAD and triphenylphospine) can yield thecyclic ether 11. Removal of the protecting group by treatment of 11 withacid (e.g. pTSA or HCl) can provide the 1,3-diol derivative 12.

A series of spiro-sulfonamide derivatives of formula 22 (X=CH₂, O; n=0,1, 2) can be prepared by the methods outlined in Scheme 3.Mono-protection of the hydroxyl group 13 can be achieved by reaction of4 or 12 with substituted benzoyl chloride in the presence of a base(e.g, TEA, DIEA, or NaOH). Oxidation of the hydroxyl group of 13 using asuitable oxidant (e.g., Dess-Martin or Swern oxidation conditions) canafford the corresponding aldehyde 14 which can be transformed intocompound 15 by reaction with trimethyl orthoformate in the presence ofp-toluenesulfonic acid (p-TsOH). Reaction of compound 15 with4-fluoro-3-nitrobenzenesulfonamide 16 in the presence of base (e.g.,potassium tert-butoxide, sodium tert-butoxide, LiHMDS or NaLiHMDS) canafford the corresponding compound 17. De-protection of the acetal groupin 17 to the aldehyde 18 can be achieved under acid conditions (e.g.,Amberlyst, p-TsOH, HCl in dioxane or TFA). Reduction of the nitro groupin 18 using a suitable reducing agent (e.g., iron in acetic acid, ironand NH₄Cl in ethanol) can yield the imine intermediate 19 which can befurther reduced to the amine derivative 20 by using suitable reductivereagent (e.g., NaBH₄ or NaBH(OAc)₃). Alternatively, the amine derivative20 can be obtained by direct hydrogenation of the nitro compound 18 inthe presence of a palladium catalyst (e.g., Pd/C or Pd(OH)₂/C in anappropriate solvent such as methanol or ethanol). Reductive amination ofthe amine derivative 20 can afford the corresponding derivative 21 whichcan be transformed into the desired product 22 by reaction with thesuitable acid using standard amide coupling conditions (e.g., EDCI, CDI,BOP, HATU or HBTU in the presence of a suitable base, TEA or DIEA).

Alternatively, a series of sulfonamide derivatives of formula 21 (X=CH₂,O; n=0, 1, 2) can be prepared by the methods outlined in Scheme 4.Reaction of the sulfonyl chloride 23 with bis-(4-methoxybenzyl)-amine(PMB)₂NH 24 can form the corresponding sulfonamide 25 which can betransformed into the derivative 30 in a similar manner as described forcompound 15 to compound 21 in the scheme 3. The removal of the PMBprotecting groups in 30 to afford the sulfonamide derivative 21 can beachieved by using acid (e.g., TFA in DCM) or hydrogenation conditions(e.g., palladium catalyzed hydrogenation Pd/C with H₂).

A series of macro-cyclic sulfonamide derivatives of formula 36 (X=CH₂,O; n=0, 1, 2; m=0, 1, 2) can be prepared by the methods outlined inScheme 5. The sulfonamide 33 can be obtained by the removal of theprotecting groups (e.g. PMB) in 32 under acid conditions (e.g. TFA, HCl)or hydrogenation conditions (e.g., palladium catalyzed hydrogenationPd/C with H₂) following the reductive amination of the sulfonamide 29with the appropriate aldehyde or ketone 31 (R^(os)=optional substituent)under suitable conditions (e.g. imine formation followed by treatmentwith a suitable reducing agent, such as NaBH₃(CN) or NaBH(OAc)₃). Theamide coupling of the sulfonamide 33 with the suitable acid 34 using acoupling agent (e.g. EDC, DCC, or HATU) in the presence of a suitablebase (e.g. TEA or DIEA) can yield the macrocyclic precursor 35 which canbe then be converted to the corresponding macrocyclic-sulfonamidederivative 36 using a suitable ring closing metathesis (RCM) catalyst(e.g. Grubbs catalyst, Grubbs-II catalyst, Grubbs-III catalyst,Hoveyda-Grubbs catalyst or Zhan catalyst 1B) under standard reactionconditions.

Similarly, a series of macrocyclic sulfonamide derivatives of formula 39(X=CH₂, O; n=0, 1, 2; m=0, 1, 2) can be prepared by the methods outlinedin Scheme 6. The amide coupling of the sulfonamide 33 with theappropriate acid 37 using a coupling agent (e.g. EDC, DCC, or HATU) inthe presence of a suitable base (e.g. TEA or DIEA) can provide thesulfonamide derivative 38 which can be then converted to thecorresponding macrocyclic sulfonamide derivative 39 in the presence ofan RCM catalyst as described in Scheme 4.

A series of macrocyclic sulfonyl carbamate derivatives of formula 42(X=CH₂, O; n=0, 1, 2; m=0, 1, 2) can be prepared similar methodsoutlined in Scheme 7. The sulfonamide 33 can react with the appropriatechloroformate derivative 40 in the presence of a suitable base (e.g.DIEA, TEA, or NaOH) to produce the corresponding sulfonyl carbamate 41which can be transformed into the desired macrocycle of formula 42 inthe presence of an RCM catalyst as described in Scheme 4.

Alternatively, the macrocyclic sulfonamide derivatives of formula 36(X=CH₂, O; n=0, 1, 2; m=0, 1, 2) can be prepared by the methods outlinedin Scheme 8. Intermolecular olefin metathesis reaction of compound 33with the vinyl derivative 43 in the presence of suitable olefinmetathesis catalyst, (e.g., Grubbs catalyst, Grubbs-II catalyst,Grubbs-III catalyst, Hoveyda-Grubbs catalyst or Zhan catalyst 1B undersuitable reaction conditions) can provide the corresponding olefincompound 44 which can be then hydrolyzed under basic conditions (e.g.,LiOH or NaOH) to provide the corresponding acid 45. Intra-molecularamide formation of 45 can afford compound 36 using a suitable amidecoupling reagent (e.g., EDCI, CDI, BOP, HATU, or HBTU) and base (e.g.,DMAP, Et₃N, or Hunig's base).

In a similar manner, a series of macrocyclic sulfonyl urea derivativesof formula 49 (X=CH₂, O; n=0, 1, 2; m=0, 1, 2) can be prepared by themethods outlined in Scheme 9. Grubbs metathesis reaction of compound 33with the vinyl derivative 46 can provide the corresponding olefincompound 47. Removal the protecting Boc-group in 47 by using acid (e.g.,TFA in DCM, HCl in dioxane) can afford the corresponding amine 48.Treatment of 48 with a suitable reagent such as CDI, phosgene ortriphosgene and a base (e.g., DMAP, Et₃N, or Hunig's base) can providethe macrocyclic sulfonyl urea derivative 49.

Alternatively, a series of macro-cyclic sulfonyl urea derivatives offormula 49 (X=CH₂, O; n=0, 1, 2; m=0, 1, 2) can be prepared by themethods outlined in Scheme 10. The sulfonyl urea derivatives 49 can beobtained by treatment of the sulfonamide 33 with diphenyl carbonate or4-nitrophenyl chloroformate in the presence of DMAP and triethylamine orHunig's base, follow by the addition of the appropriate amine 50.Alternatively, treatment of the amine 50 with phosgene, or triphosgeneto form the corresponding carbamoyl chloride which can react with thesulfonamide 33 to afford the sulfonyl urea derivatives 51. RCM reactionof 51 using methods described above can afford macrocycles of formula49.

A series of macrocyclic sulfonamide derivatives of formula 59 (X=CH₂, O;n=0, 1, 2) can be prepared by the methods outlined in Scheme 10. Thealcohol derivative 54 can be obtained by hydrolysis of the acetate ester53 which can be produced by the reductive amination of 29 with thealdehyde 52. Mitsunobo reaction (e.g., DEAD and triphenylphospine) ofcompound 54 with ester 55 (R^(os)=optional substituent) can yield theether derivative 56. Removal of the PMB groups in 56 under acidconditions (e.g. TFA, HCl) or hydrogenation conditions (e.g., palladiumcatalyzed hydrogenation Pd/C with H₂) can give 57, and hydrolysis of theester group in 57 under basic conditions (e.g., LiOH or NaOH inwater/THF) can afford the sulfonamide-acid derivative 58.Intra-molecular amide formation of 58 can form the macro-cyclicsulfonamide derivative 59 by methods provided above.

A series of spiro-cyclic sulfonamide derivatives of formula 60 can beprepared by the methods outlined in Scheme 12. Alkylation of phenolcompound 61 with a bromide 62 can give the corresponding ether 63 in thepresence of a base (e.g., NaH or NaOH) which can react with diethylmalonate 64 or other dialkyl malonate in the presence of a suitablepalladium catalyst (e.g., Pd(PtButyl)₃ or other Pd catalyst) to affordthe malonate derivative 65. 1,3-diol derivative 67 can be obtained byreduction (e.g., DIBAL, LAH, or NaBH₄) of the diethyl ester 66 providedby treatment of the malonate derivative 65 with 4-nitrobenzenesulfonylfluoride in the presence of a base (e.g., DBU or DIEA). Asymmetricmono-protecting of the OH-group 68 can be achieved by reaction of 67with substituted benzoyl chloride in the presence of a suitable chiralcatalyst, such as (R,R)-Kang Catalyst. Dess-Martin oxidation or Swernoxidation of the hydroxyl group of 68 can afford the correspondingaldehyde 69 which can be transformed to compound 70 by reaction withtrimethyl orthoformate in the presence of acid (e.g., p-TsOH inmethanol). Hydrolysis of compound 70 can yield the alcohol 71 which canbe transformed into the spiro-cyclic sulfonamide derivatives 60 in asimilar manner as the those described above for compound 15 to compound20 in Scheme 3. Reaction of the alcohol 71 with4-fluoro-3-nitrobenzenesulfonamide 25 in the presence of base (e.g.,potassium tert-butoxide, sodium tert-butoxide, LiHMDS or NaLiHMDS) canafford the corresponding compound 72. De-protection of the acetal groupin 72 to the aldehyde 73 can be achieved under acid conditions (e.g.,Amberlyst, p-TsOH, HCl in dioxane or TFA). Reduction of the nitro groupin 73 by using a suitable reducing agent (e.g., iron in acetic acid,iron or zinc and NH₄Cl in ethanol) followed by further reduction of theimine formed in situ with suitable reductive reagent (e.g., NaBH₄ orNaBH(OAc)) can afford the spiro-cyclic sulfonamide derivatives offormula 60.

A series of allyl alcohol derivatives of formula 81 or 82 can beprepared by the methods outlined in Scheme 13. Reductive amination ofthe spiro-sulfonamide 74 with aldehyde 75 using reductive agent (e.g.,NaBH₄, NaBH(OAc)₃, or NaBCNH₃) can afford the corresponding product 76which can be transformed into the alcohol 77 under saponificationconditions (e.g. acid or base). Swern oxidation or Dess-Martin oxidationof the alcohol 77 can afford the aldehyde 78. Alkylation of 78 with asuitable reagent (e.g., vinylmagnesium bromide or vinyllithium) canyield a mixture of the allyl alcohol 79 and 80. The diastereomers can beseparated by chromatography (e.g., silica gel column, or preparativeHPLC on a Cl8 column, or by SFC using a suitable column) using suitableconditions. Removal of the protecting group PMB in 79 or 80 under acidconditions (e.g., TFA in DCM or HCl in dioxane or phosphoric acid inwater) can produce the 81 or 82, respectively.

Alternatively, the allyl alcohol derivatives of formula 81 or 82 can beprepared by the methods outlined in Scheme 14 via reductive amination ofthe spiro-sulfonamide 74 with the aldehyde 85 or 86 by methods describedin Scheme 13.

The aldehyde 85 or 86 can be prepared by the methods outlined in Scheme15. Alkylation of 75 with a suitable agent (e.g., vinylmagnesium bromideor vinyllithium) can produce a mixture of the allyl alcohol 83 or 84that can be separated by chromatographic methods as described above.Oxidation of 83 or 84 under suitable conditions (e.g., Dess-Martin orSwern conditions) can afford the 85 or 86, respectively.

A series of carbamate derivatives of formula 92 can be prepared by themethods outlined in Scheme 16. Reaction of the allyl alcohol 81 or 82with acid 87 can yield the amide 88 under amide coupling conditions(e.g., BOP, HATU, HBTU, or EDCI, and an organic base such as DMAP, Et₃N,or Hunig's base). Hydrolysis under basic conditions (e.g., LiOH or NaOH)of 88 can give the alcohol 89. Macrocyclic alcohol 90 can be obtained bya RCM reaction of 89 using RCM reaction conditions described above.Macrocyclic alcohol 90 can be transformed into the desired carbamatederivative 92 by reaction with a suitable dialkylcarbamoyl chloride 93,or by reaction with diphenyl carbonate or CDI followed by treatment withsuitable amine R^(c)R^(d)NH.

Alternative, a series of carbamate derivatives of formula 98 can beprepared by the methods outlined in Scheme 17. Reaction of the allylalcohol 81 or 82 with 3-allyl-oxazolidine-2,5-dione 94 in the presenceof a suitable base (e.g., DBU or DIEA) can afford the amide 95 which canundergo a RCM reaction to yield the corresponding macrocycles 96.Reductive amination of 96 with an aldehyde RCHO with a suitable reducingagent (e.g., NaBH₃(CN) or NaBH(OAc)₃) can afford 97 which can betransformed into the desired carbamate derivative 98 by methods similarto those shown for conversion of 90 to 92 as described in Scheme 16.

A series of 2-aminoethylene ether of formula 102 can be prepared by themethods outlined in Scheme 18. Epoxide opening of compound 99(R^(os)=optional substituent) with macrocyclic alcohol 90 can give thecorresponding alcohol 100 which can be transformed into the ether 102 bya two-step process of activation of the alcohol (e.g., mesylation ortosylation) to yield 101 with a leaving group (Lg) and then displacementof the Lg with an amine R^(c)R^(d)NH to afford 102.

In a similar manner, a series of aminoalkylene ether of formula 105 canbe prepared by the methods outlined in Scheme 19. Reaction of themacrocyclic alcohol 90 with bromoalkyl trifluoromethanesulfonate 103(R^(os)=optional substituent, n=1-5) can give the bromide 104 which canbe converted to the aminoalkylene ether 105 by reaction with a suitableamine R^(c)R^(d)NH.

A series of 2-aminoethylene ether of formula 110 and amide derivative offormula 111 can be prepared by the methods outlined in Scheme 20.Reaction of the macrocyclic alcohol 90 with substituted 2-bromoaceticacid 106 (R^(os)=optional substituent) using a suitable base (e.g. NaHor DBU) can give the acid 107 which can be converted to the isobutylcarbonic anhydride 108 by treatment with isobutyl chloroformate.Reduction of the anhydride 108 with a suitable reducing agent (e.g.,DIBAL or NaBH₄) at low temperature can provide the aldehyde 109 whichcan be transformed into the 2-aminoethylene ether 110 by reductiveamination with R^(c)R^(d)NH using reductive agent (e.g., NaBH₄,NaBH(OAc)₃, or NaBCNH₃). Alternatively, reaction of the anhydride 108with amine R^(c)R^(d)NH can yield the corresponding amide 111.

Intermediate 16′-Chlorospiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

Step 1: 6′-chlorospiro[oxirane-2,1′-tetralin]

To a solution of 6-chlorotetralin-1-one (10.0 g, 55.3 mmol) in DMSO (100mL) was added trimethylsulfonium iodide (12.4 g, 60.9 mmol) andhydroxypotassium (6.21 g, 110 mmol), the mixture was stirred at 25° C.for 24 hours. The mixture was added to ice water (500 mL), extractedwith MTBE (400 mL×3), combined the organic phases, washed with brine(500 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuum togive 6′-chlorospiro[oxirane-2,1′-tetralin] (10.0 g, 51.3 mmol, 92%yield).

Step 2: 6-chlorotetralin-1-carbaldehyde

To a solution of 6′-chlorospiro[oxirane-2,1′-tetralin] (10.0 g, 51.3mmol) in THF (160 mL) was added Boron trifluoride etherate (364 mg, 2.57mmol) at −8° C., the solution was stirred at −8° C. for 10 mins. Thereaction was quenched with sat. NaHCO₃ (200 mL) at −8° C., extracted theaqueous with MTBE (400 mL×2), combined the organic phases, washed withbrine (400 mL), dried over Na₂SO₄, filtered and concentrated in vacuumto give 6-chlorotetralin-1-carbaldehyde (11.40 g, 70% purity, 40.995mmol, 79% yield).

Step 3: [6-chloro-1-(hydroxymethyl)tetralin-1-yl]methanol

To a solution of 6-chlorotetralin-1-carbaldehyde (11.4 g, 70% purity, 41mmol) in 2-(2-hydroxyethoxy)ethanol (80 mL, 41 mmol) was addedparaformaldehyde (56 mL, 41 mmol), then potassium hydroxide (56 mL, 41mmol) was added to the mixture at 5° C. The reaction mixture was stirredat 45° C. for 1 h. The reaction mixture was added brine (250 mL),extracted with DCM (300 mL×3), combined the organic phases, dried overNa₂SO₄, filtered and concentrated in vacuum, the residue was purified bysilica gel column chromatography (PE:EA=1.5:1) to give[6-chloro-1-(hydroxymethyl)tetralin-1-yl]methanol (11.2 g, 75% purity,90% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.31-7.34 (m, 2H), 7.11-7.14 (m,2H), 3.87-3.91 (m, 2H), 3.72-3.76 (m, 2H), 2.73-2.76 (m, 2H), 2.11-2.15(m, 2H), 1.89-1.92 (m, 2H), 1.79-1.83 (m, 2H).

Step 4: 6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate

To a solution of [6-chloro-1-(hydroxymethyl)tetralin-1-yl]methanol (11.2g, 37 mmol) in DCM (150 mL) was added benzoyl chloride (6.26 g, 44 mmol)at 0° C., following by drop-wise addition of DIPEA (7.4 mL, 44 mmol).The mixture stirred at 25° C. 16 h. Added DCM (150 mL) to the mixture,washed with sat. NH₄Cl (100 mL) and brine (100 mL), dried over Na₂SO₄,filtered and concentrated in vacuum, the residue was purified by silicagel column chromatography (PE:EA=9:1) to give 11.65 g of racemicproduct. ¹H NMR (400 MHz, CDCl₃): δ 8.00-8.02 (m, 2H), 7.57-7.61 (m,1H), 7.44-7.48 (m, 3H), 7.14-7.16 (m, 2H), 4.48 (s, 2H), 3.74-3.82 (m,2H), 2.78-2.81 (m, 2H), 1.83-1.95 (m, 4H).

Step 5: (6-chloro-1-formyl-tetralin-1-yl)methyl benzoate

To a solution of [6-chloro-1-(hydroxymethyl)tetralin-1-yl]methylbenzoate (1.48 g, 4.47 mmol) in DCM (25 mL) was added Dess-Martinperiodinane (2.84 g, 6.7 mmol) at 0° C., then the mixture was stirred at25° C. for 1 h. To the reaction mixture was added a 1:1 mixture of 10%Na₂S₂O₃/sat. NaHCO₃solution (100 mL). The mixture was extracted with DCM(100 mL×2). The combined organic phases were washed with brine (15 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by FC on a silica gel column to give(6-chloro-1-formyl-tetralin-1-yl)methyl benzoate (1.24 g, 84% yield). ¹HNMR (400 MHz, CDCl₃): δ 9.61 (s, 1H), 7.94-7.96 (m, 2H), 7.54-7.58 (m,1H), 7.41-7.45 (m, 2H), 7.15-7.21 (m, 3H), 4.75 (d, J=11.6 Hz, 1H), 4.55(d, J=11.6 Hz, 1H), 2.81-2.85 (m, 2H), 2.19-2.23 (m, 1H), 2.00-2.06 (m,1H), 1.89-1.95 (m, 2H).

Step 6: [6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol

To a solution of (6-chloro-1-formyl-tetralin-1-yl)methyl benzoate (1.24g, 3.77 mmol) in methanol (25 mL) were added p-TsOH H₂O (35 mg, 0.19mmol) and trimethyl orthoformate (1.2 g, 11.3 mmol). The mixture wasstirred at 70° C. for 4 h., then concentrated to 50% volume. The residuewas diluted with THF (25 mL) and 1 N NaOH (25 mL) was added. Theresulting reaction mixture was stirred at 40° C. 4 h. The solvent wasremoved. The residue was extracted with EA (20 mL×3). The combinedorganic layers were washed with 1 N NaOH (50 mL) and brine (100 mL),dried over Na₂SO₄, and concentrated under vacuum. The residue waspurified by FC on a silica gel column (PE:EA=9:1) to give[6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol (0.98 g, 96% yield).¹H NMR (400 MHz, CDCl₃): δ 7.35 (d, J=8.4 Hz, 1H), 7.10-7.13 (m, 2H),4.49 (s, 1H), 3.90 (dd, J=3.8, 11.2 Hz, 1H), 3.53 (dd, J=8.4, 11.2 Hz,1H), 3.46 (s, 3H), 3.33 (s, 3H), 2.68-2.76 (m, 2H), 1.99-2.06 (m, 1H),1.89-1.96 (m, 1H), 1.70-1.86 (m, 2H).

Step 7:4-[[6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methoxy]-3-nitro-benzenesulfonamide

A 100 mL flask with septum containing a mixture of[6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol (818 mg, 3.02 mmol)and potassium t-butoxide (779 mg, 6.94 mmol) under N₂ was charged withTHF (22 mL) giving a tan solution. The solution was stirred for 5 min at0° C., followed by addition at 0° C. of a solution of4-Fluoro-3-nitrobenzenesulfonamide (731 mg, 3.32 mmol) in THF (4 mL)over 8 min. The reaction was stirred at 0° C. for 20 min. The reactionmixture was quenched with sat. NH₄Cl (10 mL). The reaction mixture wasdiluted with water (80 mL) and sat. NH₄Cl (10 mL), and extracted withEtOAc (100 mL). The organic layer was washed with water (70 mL) and sat.NH₄Cl (10 mL), and brine (50 mL). The aqueous layers were combined, andback-extracted with EtOAc (60 mL), washed with water (60 mL), and brine(30 mL). The organic layers were combined, dried over Na₂SO₄, andfiltered and concentrated under reduced pressure to afford4-[[6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methoxy]-3-nitro-benzenesulfonamideas a yellow foam (1.52 g) and was used directly in the next reactionwithout further purification. R_(f)=0.36 (1:1 hexanes:EtOAc); ¹H NMR(500 MHz, DMSO-d₆) δ 8.28 (d, J=2.3 Hz, 1H), 8.01 (dd, J=2.4, 8.9 Hz,1H), 7.60 (dd, J=8.7, 16.3 Hz, 2H), 7.50 (s, 2H), 7.19-7.11 (m, 2H),4.63 (s, 1H), 4.38-4.26 (m, 2H), 3.38 (s, 3H), 3.29 (s, 3H), 2.70 (d,J=6.2 Hz, 2H), 2.04-1.94 (m, 1H), 1.90-1.79 (m, 2H), 1.77-1.67 (m, 1H).

Step 8:4-[(6-chloro-1-formyl-tetralin-1-yl)methoxy]-3-nitro-benzenesulfonamide

The Amberlyst 16 wet catalyst was rinsed with acetone and dried underhigh vacuum before use. A 500 mL RBF with septum containing crude4-[[6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methoxy]-3-nitro-benzenesulfonamide(1.42 g, 3.02 mmol) and pre-treated Amberlyst 16 wet (1 g, ˜7.44 mmol)under N₂ was charged with acetone (30 mL). The reaction mixture washeated at 50° C. for 2 h., filtered through cotton and rinsed with DCM.The filtrate was concentrated under reduced pressure to afford4-[(6-chloro-1-formyl-tetralin-1-yl)methoxy]-3-nitro-benzenesulfonamideas an orange/brown oil (1.7 g) which was used directly in the nextreaction without further purification. R_(f)=0.31 (1:1 hexanes:EtOAc);¹H NMR (500 MHz, DMSO-d₆) δ 9.65 (s, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.03(dd, J=2.4, 8.9 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.50 (s, 2H), 7.35-7.29(m, 2H), 7.26 (dd, J=2.4, 8.4 Hz, 1H), 4.77 (d, J=9.6 Hz, 1H), 4.47 (d,J=9.6 Hz, 1H), 2.78 (t, J=6.3 Hz, 2H), 2.19 (ddd, J=3.0, 8.9, 13.2 Hz,1H), 1.99 (ddd, J=2.8, 8.1, 13.5 Hz, 1H), 1.89-1.80 (m, 1H), 1.80-1.70(m, 1H).

Step 9;6′-chlorospiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

A solution of crude4-[(6-chloro-1-formyl-tetralin-1-yl)methoxy]-3-nitro-benzenesulfonamide(assumed 3.02 mmol) in acetic acid (50 mL) was charged with iron powder(1.69 g, 30.2 mmol). The mixture was heated at 70° C. for 3 h. Themixture was charged with Celite, diluted with DCM (50 mL), filteredthrough a Celite plug, and rinsed with DCM to yield crude6′-chlorospiro[2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide.R_(f)=0.24 (1:1 EtOAc/hexanes); LCMS calculated for C₁₈H₁₈ClN₂O₃S(M+H)⁺: m/z=377.07/379.07; found: 377.0/379.0.

The filtrate was concentrated under reduced pressure, dissolved in DCM(30 mL), cooled to 0° C., and charged with sodium triacetoxyborohydride(1.99 g, 9.44 mmol) over 1 min. The reaction mixture was stirred at 0°C. for 1 min, then stirred at RT for 80 min. The reaction mixture wasquenched with 10% citric acid (30 mL), diluted with water (30 mL), andextracted with EtOAc (125 mL). The organic layer was washed with 10%citric acid (10 mL) and water (40 mL), washed with brine (2×40 mL),dried over Na₂SO₄, and filtered. The filtrate was concentrated underreduced pressure to yield6′-chlorospiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(1.24 g, 2.61 mmol, 86% yield) as a light tan foam. R_(f)=0.45 (1:1EtOAc/hexanes). LCMS calculated for C₁₈H₂₀ClN₂O₃S (M+H)⁺:m/z=379.09/379.08; found: 379.0/381.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.81(d, J=8.5 Hz, 1H), 7.26 (dd, J=2.4, 8.5 Hz, 1H), 7.18 (dd, J=2.3, 15.2Hz, 2H), 7.13 (s, 2H), 7.02 (dd, J=2.3, 8.4 Hz, 1H), 6.92 (d, J=8.4 Hz,1H), 6.20 (t, J=4.1 Hz, 1H), 4.08 (q, J=12.2 Hz, 2H), 3.23 (dd, J=4.7,13.7 Hz, 1H), 2.77-2.65 (m, 2H), 1.87-1.66 (m, 3H), 1.55 (ddd, J=2.9,9.7, 12.7 Hz, 1H).

Intermediate 2(3S)-6′-Chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

Step 1:4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide

To a cooled (−35° C.) solution of 4-Fluoro-3-nitrobenzenesulfonylchloride (4.89 g, 20.42 mmol) in THF (50 mL) was added Triethylamine(3.13 mL, 22.46 mmol), followed by addition ofBis-(4-methoxybenzyl)amine (4.97 mL, 20.7 mmol) in THF (50 mL) solutionover 30 min. while the temperature was kept at −35° C. After completionof the addition, the temperature was allowed slowly to warm to 0° C.over 1 h., and the mixture was stirred at 0° C. for an additional hour.The mixture was neutralized with 1 N HCl to pH about 4-5 and dilutedwith EtOAc (100 mL). The organic layer was separated, washed with 1 NHCl (10 mL), 7.5% NaHCO₃aqueous solution (20 mL), and brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas treated with DCM (30 mL), and hexane was added to the suspensionuntil it became cloudy. The resulting suspension was sonicated for 2min. and left at r.t. for 1 h. The mixture was filtered. and washed withhexane to afford the desired title product (6.85 g) without furtherpurification. The mother liquid was concentrated under reduced pressure.The residue was treated with DCM (5 mL) and hexane was added as theprocedures mentioned above to afford the additional 0.51 g of the titleproduct. Total product4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamideobtained is 7.36 g (78%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.18-8.23 (m,2H), 7.75-7.79 (q, 1H), 7.08 (d, 4H), 6.81 (d, 4H), 4.31 (s, 4H), 3.71(s, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −112.54 (s, 1 F). LCMS calculatedfor C₂₂H₂₂FN₂O₆S (M+H)⁺: m/z=461.11; found: 461.1.

Step 2: [(1S)-6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoateand [(1R)-6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate

Racemic product 6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate(intermediate 1, Step 4) was separated by Waters-SFC80 instrument underthe separation conditions: Column: AD-H (2.5*25 cm, 10 um); Mobile phaseA: Supercritical CO₂, Mobile phase B: EtOH, A:B=80/20 at 60 mL/min;Circle Time: 15 min; Sample preparation: Ethanol; Injection Volume: 0.8mL; Detector Wavelength: 214 nm; Column temperature: 25° C.; Backpressure: 100 bar. The separated products were determined by chiralHPLC. Chiral HPLC conditions: Chiral Column: AD-H, 5 um, 4.6 mm×250 mm(Daicel); Mobile phase: Supercritical C02/EtOH/DEA 70/30/0.06; Flowrate: 2.0 mL/min and Run time: 12 min. to afford[(1S)-6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate (P1,Retention time=4.952 min.) and[(1R)-6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate (P2,Retention time=6.410 min.). ¹H NMR (400 MHz, CDCl₃): δ 8.00-8.02 (m,2H), 7.57-7.61 (m, 1H), 7.44-7.48 (m, 3H), 7.14-7.16 (m, 2H), 4.48 (s,2H), 3.74-3.82 (m, 2H), 2.78-2.81 (m, 2H), 1.83-1.95 (m, 4H).

Step 3: [(1R)-6-chloro-1-formyl-tetralin-1-yl]methyl benzoate

This compound was prepared using procedures analogous to those describedfor Intermediate 1 using[(1S)-6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate (Step 2,P1) to replace the racemic[6-chloro-1-(hydroxymethyl)tetralin-1-yl]methyl benzoate in Step 5. ¹HNMR (400 MHz, CDCl₃): δ 9.61 (s, 1H), 7.94-7.96 (m, 2H), 7.55-7.58 (m,1H), 7.41-7.45 (m, 2H), 7.15-7.20 (m, 3H), 4.73-4.76 (d, 1H), 4.53-4.56(d, 1H), 2.82-2.85 (m, 2H), 2.20-2.26 (m, 1H), 2.01-2.07 (m, 1H),1.90-1.96 (m, 2H).

Step 4: [(1R)-6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol

Method A: This compound was prepared using procedures analogous to thosedescribed for Intermediate 1 using[(1R)-6-chloro-1-formyl-tetralin-1-yl]methyl benzoate to replace theracemic (6-chloro-1-formyl-tetralin-1-yl)methyl benzoate in Step 6. ¹HNMR (400 MHz, CDCl₃+D₂O): δ 7.34-7.36 (m, 1H), 7.10-7.12 (m, 2H), 4.49(s, 1H), 3.89-3.91 (d, 1H), 3.50-3.53 (m, 1H), 3.46 (s, 3H), 3.33 (s,3H), 2.68-2.76 (m, 2H), 1.99-2.06 (m, 1H), 1.89-1.96 (m, 1H), 1.70-1.86(m, 2H).

Method B: The racemic (6-chloro-1-formyl-tetralin-1-yl)methyl benzoate(Intermediate 1 Step 6) was separated by chiral column on Berger MG2Preparative SFC instrument under the separation conditions: Column:ChiralPak IC (2×25 cm); Mobile phase A: i-PrOH, Mobile phase B:Supercritical CO₂, A:B=1/3 at 60 mL/min; Circle Time (Run Time): 5 mininjection intervals; Sample preparation: 20 mg/mL iPrOH/DCM; InjectionVolume: 0.5 mL; Detector Wavelength: 220 nm; Column temperature: 30° C.;Back pressure: 100 bar. The separated products were determined by chiralHPLC on Berger Analytical SFC. Chiral HPLC conditions: Chiral Column:ChiralPak IC, 5 um, 4.6 mm×250 mm (Daicel); Mobile phase:i-PrOH/Supercritical CO₂/EtOH 1/3; Flow rate: 3.0 mL/min and Run time: 7min.; Detector Wavelength (UV length): 220 nm, 254 nm, and 280 nm;Column temperature: 30° C.; Back pressure: 120 bar. to afford[(1S)-6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol (P1, Retentiontime=1.96 min.) and[(1R)-6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol (P2, Retentiontime=2.69 min.)

Step 5:N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-(dimethoxymethyl)-tetralin--yl]methoxy]benzenesulfonamide

To a solution of [(R)-6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methanol(2.96 g, 10.93 mmol, P2) in THF (50 mL) was drop-wised add LiHMDS (11.5mL, 11.4 mmol) under N₂ atmosphere at −40° C., the solution was stirredat −40° C. for 5 mins, then dropwise added4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide(7.55 g, 16.4 mmol) (Step 1) in THF (30 mL). The solution was stirredfor 5 min. under −40° C., then the mixture was stirred at r.t. for 1 h.The reaction was cooled with ice-water bath, and quenched with sat.NH₄Cl aqueous solution (100 mL). The mixture was extracted with EtOAc(100 mL×3). The combined organic layers were washed with sat. NH₄Clsolution and brine, dried over Na₂SO₄, filtered and concentrated invacuum. The residue was purified by flash chromatography on a silica gelcolumn eluting with ethyl acetate (EA) and petroleum ether (PE) to giveN,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methoxy]benzenesulfonamide(6.41 g, 82% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.06-8.07 (m, 1H),7.97-8.00 (m, 1H), 7.60-7.62 (m, 1H), 7.49-7.51 (m, 1H), 7.14-7.17 (m,2H), 6.99-7.07 (m, 4H), 6.77-6.79 (m, 4H), 4.62 (s, 1H), 4.27-4.36 (m,2H), 4.24 (s, 4H), 3.70 (s, 6H), 3.39 (s, 3H), 3.30 (s, 3H), 2.68-2.71(m, 2H), 1.98-2.00 (m, 1H), 1.81-1.85 (m, 2H), 1.71-1.73 (m, 1H).

Step 6: N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-formyl-tetralin-1-yl]methoxy]benzenesulfonamide

To a solution ofN,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-(dimethoxymethyl)tetralin-1-yl]methoxy]benzenesulfonamide(6.11 g, 8.59 mmol) in THF (80 mL) and water (20 mL) was added p-TsOHH₂O (3.27 g, 17.18 mmol), the mixture was stirred at 70° C. for 16 h.The mixture was cooled to 0° C., and sat. NaHCO₃aqueous (100 mL) wasadded. The mixture was extracted with EA (100 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column eluting with EA and to give N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-formyl-tetralin-1-yl]methoxy]benzenesulfonamide(6.11 g, 85% purity, 91% yield).

Step 7:(S)-6′-chloro-N,N-bis(4-methoxybenzyl)-3′,4′-dihydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-sulfonamide

To a solution ofN,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(1R)-6-chloro-1-formyl-tetralin-1-yl]methoxy]benzenesulfonamide(6.11 g, 7.81 mmol) in ethanol (40 mL) and water (20 mL) was added ironpowder (2.18 g, 39 mmol) and NH₄Cl (827 mg, 15.6 mmol), the mixture wasstirred at 100° C. for 3 h. LCMS showed the reaction completed. Themixture was filtered. The filtrate was added H₂O (20 mL), extracted withEA (30 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give(S)-6′-chloro-N,N-bis(4-methoxybenzyl)-3′,4′-dihydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-sulfonamide(6.11 g, 70% purity, 86% yield) which was directly used in next stepreaction without further purification. LCMS calculated for C₃₄H₃₄ClN₂O₅S(M+H)⁺: m/z=617.18; found: 617.3.

Step 8:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of(S)-6′-chloro-N,N-bis(4-methoxybenzyl)-3′,4′-dihydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-sulfonamide(6.11 g, 6.73 mmol) (crude product from Step 7, 70% purity) in DCM (80mL) was portion-wise added NaBH(OAc)₃ (7.14 g, 33.67 mmol). The mixturewas stirred at 25° C. for 16 h. LCMS showed the reaction worked well.The reaction was added sat. NaHCO₃aqueous (80 mL), extracted with DCM(100 mL×3), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column eluting with EA and PE to give(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(2.30 g, 53% yield). LCMS calculated for C₃₄H₃₆ClN₂O₅S (M+H)⁺:m/z=619.2; found: 619.3. ¹H NMR (400 MHz, DMSO-d₆): δ 7.81-7.83 (m, 1H),7.24-7.28 (m, 2H), 7.17-7.18 (m, 1H), 6.95-7.06 (m, 6H), 6.78-6.80 (m,4H), 6.20 (s, 1H), 4.15 (m, 4H), 4.08-4.14 (m, 2H), 3.68 (s, 6H),3.30-3.36 (m, 1H), 3.23-3.27 (m, 1H), 2.71-2.75 (m, 2H), 1.76-1.86 (m,3H), 1.56-1.61 (m, 1H).

Intermediate 3(3S)-6′-Chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamideand Intermediate 4(3S)-6′-Chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

Step 1:[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylacetate

2,2,2-trifluoroacetic acid (7.0 mL, 92 mmol) was dropwise added to astirred solution of sodium borohydride (3.48 g, 92.0 mmol) in DCM (200mL) at 0° C. The resulting mixture was stirred at 0° C. for 10 min. Asolution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(28.5 g, 46.03 mmol) and [(1R,2R)-2-formylcyclobutyl]methyl acetate(8.63 g, 55.24 mmol) in 200 mL DCM was then dropwise added at 0° C. Theresulting mixture was stirred at room temperature for overnight. Thereaction was monitored by LC-MS. Another 2 equivalents of sodiumborohydride (3.48 g, 92.06 mmol) and 2,2,2-trifluoroacetic acid (7.04mL, 92.06 mmol) were added to the mixture, followed by the stirring for3 h. The reaction was quenched by addition of methanol (30 mL), andfollowed by addition of saturated NaHCO₃solution (300 mL) slowly. Theresulting mixture was extracted with DCM (300 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column using EtOAc/Heptanes (5-40%) to afford the desiredproduct[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylacetate (34.5 g, 45.4 mmol, 98% yield) as a white solid. LC-MS calc. forC₄₀H₄₃ClN₂O₆S [M+H]⁺: m/z=759.28/760.28; Found 759.67/760.64.

Step 2:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylacetate (54.0 g, 71.1 mmol) in THF (500 mL), methanol (500 mL) and water(500 mL) was added lithium hydroxide monohydrate (14.9 g, 355 mmol). Themixture was stirred at r.t. overnight. The solvent was removed, and theaqueous layer was extracted with DCM (100 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(52 g, 101% yield) as white solid which was directly used for the nextstep without further purification. LC-MS calc. for C₄₀H₄₅ClN₂O₆S [M+H]⁺:m/z=717.27/718.27; Found 717.6/718.6.

Step 3:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

DMSO (20.5 mL, 289 mmol) was slowly added to a cooled (−78° C.) solutionof oxalyl chloride (12.4 mL, 144.9 mmol) in DCM (1000 mL). Gas wasproduced during this addition. The mixture was stirred at −78° C. for 30min. Then a solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(52.0 g, 72.4 mmol) in DCM (50 mL) was added over 5 min. The resultingmixture was stirred at −78° C. for 40 min. Then triethylamine (101 mL,724 mmol) was added. The solution was stirred at −78° C. for additional10 min, and allowed to warm slowly to 0° C. After the starting materialwas consumed, water (150 mL) was added. The organic layer wereseparated. The aqueous layer was extracted with DCM (300 mL×3). Thecombined organic layers were dried over sodium sulfate and concentrated.The residue was purified by flash chromatography on a silica gel columnwith EtOAc/Heptanes (5-50%) to afford(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(43 g, 83% yield) as a white solid. LC-MS calc. for C₄₀H₄₃ClN₂O₆S[M+H]⁺: m/z=715.25/716.26; Found 715.7/716.7.

Step 4:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamideand(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

Vinylmagnesium bromide (1.0 M solution in THF, 300 mL, 300 mmol) wasdiluted with THF (200 mL) in a 3 necked round bottom flack undernitrogen.(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(43.0 g, 60.1 mmol) dissolved in THF (400 mL) was introduced dropwisethrough a dropping funnel over 2 hours at room temperature. The reactionwas monitored by LC-MS. After the starting material was consumed, thereaction was then quenched by addition of sat. aqueous solution NH₄Cl(300 mL) at 0° C. The organic layer was then separated, and the aqueouslayer was extracted with ethyl acetate (300 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column using EtOAc/Heptanes (5-40%) to afford two products: P1 (theearlier eluted product: 24.3 g, 40%) and P2 (the latter eluted product:20 g, 33%).

P1 was assigned as(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Rt=4.43 min from LC-MS). LC-MS calc. for C₄₂H₄₈ClN₂O₆S [M+H]⁺:m/z=743.28/744.29; Found 743.76/744.78. ¹H NMR (300 MHz, CDCl₃) δ 7.76(t, J=7.2 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.24-7.14 (m, 2H), 7.12 (d,J=2.0 Hz, 1H), 7.03-6.97 (m, 5H), 6.79 (t, J=5.7 Hz, 4H), 5.84-5.69 (m,1H), 5.16 (d, J=17.2 Hz, 1H), 5.05 (d, J=10.4 Hz, 1H), 4.26 (t, J=5.6Hz, 4H), 4.13 (s, 2H), 3.97 (d, J=4.4 Hz, 1H), 3.80 (d, J=1.8 Hz, 6H),3.74 (d, J=6.2 Hz, 1H), 3.26 (d, J=14.2 Hz, 1H), 3.09 (dd, J=15.0, 9.3Hz, 1H), 2.93 (d, J=4.2 Hz, 1H), 2.83-2.75 (m, 2H), 2.48-2.35 (m, 1H),2.10-1.92 (m, 4H), 1.82 (m, 3H), 1.50 (m, 2H).

And P2 was assigned as(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Rt=4.13 min from LC-MS). LC-MS calc. for C₄₂H₄₈ClN₂O₆S [M+H]⁺:m/z=743.28/745.29; Found 743.8/745.8. ¹H NMR (300 MHz, CDCl₃) δ7.75-7.68 (m, 1H), 7.24-7.14 (m, 3H), 7.12 (d, J=2.0 Hz, 1H), 7.01 (t,J=8.3 Hz, 5H), 6.79 (d, J=8.7 Hz, 4H), 5.85 (ddd, J=17.0, 10.4, 6.4 Hz,1H), 5.29 (dd, J=17.2, 1.2 Hz, 1H), 5.17-5.08 (m, 1H), 4.26 (d, J=8.4Hz, 4H), 4.14 (d, J=8.0 Hz, 3H), 3.81 (s, 6H), 3.69 (d, J=14.3 Hz, 1H),3.59 (d, J=12.9 Hz, 1H), 3.31 (d, J=14.3 Hz, 1H), 3.15 (dd, J=14.9, 9.0Hz, 1H), 2.84-2.76 (m, 2H), 2.67-2.56 (m, 1H), 2.23-2.09 (m, 2H), 2.03(m, 2H), 1.86-1.73 (m, 3H), 1.59-1.46 (m, 2H).

Step 5:(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 3)

To a solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(24.3 g, 32.6 mmol, P1, Step 4) and anisole (23.7 mL, 218 mmol) in DCM(240 mL) was added 2,2,2-trifluoroacetic acid (243 mL). The mixture wasstirred overnight. The reaction was monitored by LC-MS. Solvents wereremoved under reduced pressure. The residue was diluted with DCM (200mL). The mixture was washed with saturated aqueous NaHCO₃solution (200mL×3) and brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column with EA/heptane (5%-70%) to afford(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(15.7 g, 31.2 mmol, 95% yield) as a pale white solid. LC-MS calc. forC₂₆H₃₂ClN₂O₄S [M+H]⁺: m/z=503.17/505.17; Found 503.5/505.5; ¹H NMR (300MHz, CDCl₃) δ 7.74 (d, J=8.5 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.21 (dd,J=11.4, 4.2 Hz, 2H), 7.12-7.08 (m, 2H), 6.97-6.94 (m, 1H), 6.85 (d,J=8.6 Hz, 1H), 5.90-5.76 (m, 1H), 5.25 (d, J=17.2 Hz, 1H), 5.16-5.08 (m,1H), 4.11 (s, 2H), 3.88 (d, J=5.1 Hz, 1H), 3.81 (s, 2H), 3.27 (d, J=14.3Hz, 1H), 3.14 (m, 1H), 2.84-2.75 (m, 2H), 2.51 (dd, J=16.9, 8.5 Hz, 1H),2.08 (m, 3H), 1.90 (dd, J=15.8, 5.6 Hz, 2H), 1.63 (m, 3H), 1.45 (t,J=12.1 Hz, 1H).

Step 6:(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 4)

This compound was prepared using procedures analogous to those describedfor step 5 using P2 Step 4. LC-MS calc. for C₂₆H₃₂ClN₂O₄S [M+H]⁺:m/z=503.17/505.17; Found 503.5/505.5; ¹H NMR (300 MHz, CDCl₃) δ 7.72 (d,J=8.5 Hz, 1H), 7.27-7.16 (m, 3H), 7.12 (s, 1H), 6.99-6.94 (m, 1H),5.94-5.79 (m, 1H), 5.31 (d, J=17.2 Hz, 1H), 5.19 (d, J=10.5 Hz, 1H),4.34-4.26 (m, 1H), 4.15-4.08 (m, 2H), 3.70 (d, J=14.5 Hz, 2H), 3.28 (d,J=14.2 Hz, 1H), 3.16 (dd, J=15.1, 9.0 Hz, 1H), 2.79 (dd, J=9.3, 5.0 Hz,2H), 2.75-2.65 (m, 1H), 2.31-2.21 (m, 1H), 2.05-1.88 (m, 3H), 1.80-1.71(m, 2H), 1.71-1.59 (m, 2H), 1.50 (t, J=11.4 Hz, 1H).

Intermediate 5[(1S)-1-[(1R,2R)-2-[[(3S)-6′-Chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetate

Step 1:[(1S)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetate

To a stirred solution of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(1.20 g, 1.61 mmol, Intermediate 3 and 4, Step 4, P1) in DCM (40 mL) wasadded DMAP (39 mg, 0.32 mmol), triethylamine (0.27 mL, 2.1 mmol) andAc₂O (0.18 mL, 1.8 mmol). The reaction mixture was then stirred at r.t.for 6 h. The reaction was diluted with DCM (40 mL), washed with water(30 mL) and brine. The combined organic layers were dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure toafford the desired product (1.26 g) as a light orange colored solid.LC-MS calc. for C₄₄H₅₀ClN₂O₇S [M+H]⁺: m/z=785.29/787.29. Found:785.2/787.4.

Step 2:[(1S)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetate

To a stirred solution of[(1S)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetate (1.26 g, 1.6 mmol) in DCM (20 mL) was added TFA (20 mL, 137mmol) dropwise. The reaction was stirred at 40° C. overnight. LC-MSshowed the starting material was consumed. The reaction was cooled tor.t. and slowly poured into a 120 mL of saturated K₂CO₃ solution underan ice bath. The mixture was extracted with DCM (30 mL×3). The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified by flash chromatographyon a silica gel column (12 g) using EtOAc/Heptanes (2% to 50%) to afford[(1S)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetate (680 mg, 77% yield). LC-MS calc. for C₂₈H₃₄ClN₂O₅S [M+H]⁺:mz=545.18/547.18. Found: 544.8/546.4.

Intermediate 6[(1R)-1-[(1R,2R)-2-[[(3S)-6′-Chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetate

This compound was prepared using procedures analogous to those describedfor Intermediate 5 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 3 and 4, Step 4, P2) in Step 1. LC-MS calc. forC₂₈H₃₄ClN₂O₅S [M+H]⁺: m/z=545.18/547.18. Found: 544.8/546.6.

Intermediate 7(3R)-6′-Chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

Step 1:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a cooled (ice-water bath) solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(3.2 g, 4.3 mmol, Intermediate 3 and 4, Step 4, P1) in THF (70 mL) wasadded sodium hydride (0.52 g, 12.9 mmol). The mixture was stirred for 5min., then iodomethane (0.8 mL, 12.9 mmol) was added. The mixture wasstirred at 50° C. overnight. The reaction was quenched by addition ofsaturated aqueous ammonium chloride (70 mL) and water (70 mL). Themixture was extracted with EA (70 mL×3). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford the crude product(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(3.1 g, 95% yield) which was directly used in next step directly withoutfurther purification. LC-MS calc. for C₄₃H₅₀ClN₂O₆S [M+H]⁺:m/z=757.3/759.3. Found: 757.0/759.4.

Step 2:(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

This compound was prepared using procedures analogous to those describedfor Intermediate 5 Step 2 using(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide.LC-MS calc. for C₂₇H₃₄ClN₂O₄S [M+H]⁺: m/z=517.2/519.2. Found:516.8/518.7.

Intermediate 8(3S)-6′-Chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

This compound was prepared using procedures analogous to those describedfor Intermediate 7 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 3 and 4, Step 4, P2) in Step 1. LC-MS calc. forC₂₇H₃₅ClN₂O₄S [M+H]⁺: m/z=517.2/519.2. Found: 516.8/518.5.

Intermediate 9[(1S)-1-[(1R,2R)-2-[[(3S)-6′-Chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate

Step 1:[(1S)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate

To a stirred solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(0.8 g, 1.08 mmol, Intermediate 3 and 4, Step 4, P1) in THF (10mL)/Toluene (10 mL) was added N,N-dimethylcarbamoyl chloride (1.16 g,10.7 mmol). The resulting mixture was cooled to −78° C. and KHMDS (8.15mL, 0.5 M in Toluene) was added dropwise over 10 min. The reaction wasstirred at −78° C. for 10 min. Then the solution was slowly warmed up tor.t. and stirred for 1 h. LC-MS showed the consumption of startingmaterial and the formation of desired product. The reaction was quenchedwith saturated ammonium chloride solution (20 mL) and extracted withEtOAc (20 mL×3). The combined organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column (20 g) usingEtOAc/Heptanes (10% to 60%) to afford[(1S)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate (0.69 g, 78% yield) as a white solid. LC-MS calc.for C₄₅H₅₃ClN₃O₇S [M+H]⁺: m/z=814.3/816.3; Found: 814.8/816.9.

Step 2:[(1S)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Intermediate 5 Step 2. LC-MS calc. for C₂₉H₃₇ClN₃O₅S [M+H]⁺:m/z=574.2/576.2; Found: 574.6/576.5.

Intermediate 10[(1R)-1-[(1R,2R)-2-[[(3S)-6′-Chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate

Step 1:[(1R)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Intermediate 9 Step 1 using(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 3 and 4, Step 4 P2) and N,N-dimethylcarbamoyl chloride.LC-MS calc. for C₄₅H₅₃ClN₃O₇S [M+H]⁺: m/z=814.3/816.3; Found:814.7/816.1.

Step 2:[(1R)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Intermediate 5 Step 2. LC-MS calc. for C₂₉H₃₇ClN₃O₅S [M+H]⁺:m/z=574.2/576.2; Found: 574.8/576.7.

Intermediate 11(S)-7′-Chloro-N,N-bis(4-methoxybenzyl)-4,5-dihydro-2H-spiro[benzo[b][1,4]oxazepine-3,4′-chromane]-7-sulfonamide

Step 1: (2-(2-bromo-5-chlorophenoxy)ethoxy)(tert-butyl)dimethylsilane

To a solution of 2-bromo-5-chlorophenol (20.0 g, 96.4 mmol) in NMP (100mL) was added K₂CO₃ (26.6 g, 192 mmol) and2-bromoethoxy-tert-butyldimethylsilane (22.7 mL, 106 mmol). Theresulting suspension was stirred at 90° C. for 5 h. After cooling tor.t., the suspension was diluted with water (150 mL), and extracted withethyl acetate (3×150 mL). The combined organic layers were washed withwater (150 mL), brine (150 mL) and dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on a silica gel column with PE/EA (5%) to afford2-(2-bromo-5-chloro-phenoxy)ethoxy-tert-butyl-dimethyl-silane (32 g, 90%yield) as light yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (d, J=8.4Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.95 (dd, J=8.4, 2.4 Hz, 1H), 4.18-4.16(m, 2H), 3.94-3.93 (m, 2H), 0.86 (s, 9H), 0.06 (s, 6H).

Step 2: diethyl2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)malonate

To a suspension of K₃PO₄ (21.35 g, 100.6 mmol) andbis(tri-tert-butylphosphine)palladium(0) (1.70 g, 3.34 mmol) in toluene(100 mL), was added2-(2-bromo-5-chloro-phenoxy)ethoxy-tert-butyl-dimethyl-silane (12.2 g,33.3 mmol), followed by the addition of diethyl malonate (10.68 g, 66.7mmol). The resulting suspension was heated at 85° C. for 6 h. under anatmosphere of argon, and then cooled to r.t. The mixture was filteredthrough a pad of Celite and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography on a silicagel column with Hexane/EA (0-10%) to afford diethyl2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-chloro-phenyl]propanedioate(7.3 g, 49.2% yield) as a clear oil. ¹H NMR: (400 MHz, CDCl₃) δ 7.30 (d,J=8.2 Hz, 1H), 6.96 (dd, J=8.3, 2.0 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H),5.11 (s, 1H), 4.27-4.15 (m, 4H), 4.04 (t, J=5.0 Hz, 2H), 3.94 (t, J=5.1Hz, 2H), 1.26 (t, J=7.2 Hz, 6H), 0.91 (s, 9H), 0.09 (s, 6H).

Step 3: diethyl 7-chlorochromane-4,4-dicarboxylate

To a solution of diethyl2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-chloro-phenyl]propanedioate(9.53 g, 21.4 mmol) and DBU (6.52 g, 42.8 mmol) in MeCN (200 mL) underN₂ atmosphere was added 4-nitrobenzenesulfonyl fluoride (8.79 g, 42.8mmol). The resulting solution was stirred at 70° C. for 24 h. Aftercooling, the solution was concentrated at 35° C. under reduced pressureto remove MeCN. The residue was diluted with water (120 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water (100 mL), 1 N HCl (100 mL), followed by NaHCO₃(500 mL) solution and brine (100 mL). The organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography on a silica gel column withHexane/EA (0-10%) (Rf=0.4 in 10% ethyl acetate in hexane) to afforddiethyl 7-chlorochromane-4,4-dicarboxylate (7.400 g, 110.5% yield). ¹HNMR: (400 MHz, CDCl₃) δ 7.36 (d, J=8.4 Hz, 1H), 6.90 (dd, J=2.0 Hz, 8.4Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 4.28-4.19 (m, 6H), 2.54-2.51 (m, 2H),1.27 (t, J=7.2 Hz, 6H).

Step 4: [7-chloro-4-(hydroxymethyl)chroman-4-yl]methanol

To a solution of diethyl 7-chlorochromane-4,4-dicarboxylate (6.30 g,20.1 mmol) in THF (25 mL) was added diisobutylaluminum hydride (201.4mL, 201 mmol, 1 M in THF) dropwise at 0° C. The reaction mixture wasstirred at r.t. for 18 h. Then it was quenched by the addition ofsaturated solution of NH₄Cl (200 mL) and extracted with ethyl acetate(3×280 mL). The combined organic layers were concentrated under reducedpressure. The crude material was dissolved in THF (100 mL) and water(200 mL), and sodium borohydride (4.4 g, 114.8 mmol) was added. Thereaction was stirred at r.t. for 3 h., and then quenched with saturatedNH₄Cl solution (75 mL). The mixture was extracted with ethyl acetate(2×60 mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on a silica gel column with Hexane/EA(0-70%) to afford [7-chloro-4-(hydroxymethyl)chroman-4-yl]methanol (2.80g, 61% yield). ¹H NMR: (400 MHz, CDCl₃) δ 7.23 (d, J=9.2 Hz, 1H),6.87-6.85 (m, 2H), 4.21 (t, J=5.2 Hz, 2H), 3.97 (d, J=10.8 Hz, 2H), 3.78(d, J=10.8 Hz, 2H), 2.09 (t, J=5.2 Hz, 2H).

Step 5: (S)-(7-chloro-4-(hydroxymethyl)chroman-4-yl)methyl4-bromobenzoate

To a solution of2,6-bis((R)-5,5-dibutyl-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine (934mg, 1.57 mmol) in dry DCM (3 mL) was added CuCl₂ (211 mg, 1.57 mmol) andthe resulting green solution was stirred at r.t. for 3 h. This solutionwas added to a solution of[7-chloro-4-(hydroxymethyl)chroman-4-yl]methanol (3.60 g, 15.74 mmol) indry DCM (60 mL). The resulting solution was cooled to −78° C. A solutionof 4-bromobenzoyl chloride (4.15 g, 18.8 mmol) in DCM (5 mL) was thenadded slowly, followed by the dropwise addition of DIPEA (3.29 mL, 18.8mmol). The resulting reaction mixture was stirred at −78° C. for 2 h.and then quenched with KH₂PO₄/H₃PO₄ buffer solution (70 mL, pH˜3). Thereaction was diluted with ethyl acetate (150 mL) and the layers wereseparated. The organic phase was washed with pH˜3 buffer (1×50 mL),saturated NaHCO₃ (2×50 mL) and brine (1×50 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure The residuewas purified by column chromatography on a silica gel column elutingwith 100% DCM to afford[(4S)-7-chloro-4-(hydroxymethyl)chroman-4-yl]methyl 4-bromobenzoate(4.10 g, 63% yield) (e.r.=92:8). The chiral HPLC: Chiral Column: AD, 2.5um, 3.0 mm×150 mm; Mobile phase A: Supercritical CO₂, Mobile phase B:MeOH (with 0.1% DEA), A:B=50:50; Run time: 20 min.; Detector Wavelength:254 nm, Instrument: Waters Acouity UPC². ¹H NMR: (400 MHz, CDCl₃) δ 7.86(d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.0Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 4.53 (d, J=6.0 Hz, 2H), 4.23 (d, J=6.0Hz, 2H), 3.80 (s, 2H), 2.16-2.09 (m, 1H), 2.02-1.97 (m, 1H).

Step 6: (R)-(7-chloro-4-formylchroman-4-yl)methyl 4-bromobenzoate(GXL002-55-1)

Dess-Martin periodinane (5.07 g, 11.95 mmol) was added to a stirringsolution of [(4S)-7-chloro-4-(hydroxymethyl)chroman-4-yl]methyl4-bromobenzoate (4.10 g, 9.96 mmol) in DCM (130 mL) at 10° C. Afteraddition, the cooling bath was removed and the reaction mixture wasstirred for 30 min. at ambient temperature. Water (17 ml) was then addedslowly and the reaction mixture was stirred further at ambienttemperature for 30 min. The reaction was cooled to 0° C., quenched witha 1:1 mixture of 10% Na₂S₂O₃ and saturated NaHCO₃ (20 mL) solution andstirred further at r.t. for 1 h. The solution was then diluted withethyl acetate (700 mL) and the aqueous phase was separated. The organicphase was washed with 1:1 mixture of 10% Na₂S₂O₃/saturatedNaHCO₃solution (200 mL) and brine (20 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure The residue waspurified by column chromatography on a silica gel column with elutingwith ethylacetate in hexanes (10%) to afford[(4R)-7-chloro-4-formyl-chroman-4-yl]methyl 4-bromobenzoate (3.0 g, 73%yield). ¹H NMR: (400 MHz, CDCl₃) δ 9.60 (s, 1H), 77.81 (d, J=6.8 Hz, 2H)7.58 (d, J=8.4 Hz, 2H), 7.13 (dd, J=1.2 Hz, 7.6 Hz, 1H), 6.94 (d, J=8.4Hz, 2H), 4.84 (d, J=11.2 Hz, 1H), 4.54 (d, J=11.2 Hz, 1H), 4.27-4.24 (m,2H), 2.52-2.46 (m, 1H), 2.12-2.06 (m, 1H).

Step 7: (R)-(7-chloro-4-(dimethoxymethyl)chroman-4-yl)methyl4-bromobenzoate

To a mixture of [(4R)-7-chloro-4-formyl-chroman-4-yl]methyl4-bromobenzoate (3.0 g, 7.3 mmol) and trimethyl orthoformate (2.33 g,21.9 mmol) in anhydrous MeOH (10 mL) was added p-toluenesulfonic acid(63 mg, 0.37 mmol). The reaction was refluxed for 6 h., and concentratedunder reduced pressure. The residue was purified by columnchromatography on a silica gel column with eluting with ethylacetate/hexane (10%) to afford[(4R)-7-chloro-4-(dimethoxymethyl)chroman-4-yl]methyl 4-bromobenzoate(2.5 g, 74% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.75(d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4Hz, 1H), 6.87-6.83 (m, 1H), 6.51 (d, J=4.4 Hz, 1H), 4.53-4.49 (m, 2H),4.32-4.29 (m, 1H), 4.20-4.18 (m, 1H), 3.45 (s, 3H), 3.30 (s, 3H),2.34-2.29 (m, 1H), 2.02-1.97 (m, 1H).

Step 8: (R)-(7-chloro-4-(dimethoxymethyl)chroman-4-yl)methanol

To a mixture of [(4R)-7-chloro-4-(dimethoxymethyl)chroman-4-yl]methyl4-bromobenzoate (2.50 g, 5.49 mmol) in water (17 mL) and THF (34 mL) wasadded NaOH (658 mg, 16.4 mmol). The resulting mixture was stirred atr.t. overnight, and then concentrated under reduced pressure. Theresidue was diluted with EtOAc (50 mL) and washed with water (10 mL), 1N NaOH (10 mL), water (10 mL) and brine. The organic layer was driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by column chromatography on a silica gel columneluting with PE:EA (2:1) to afford[(4R)-7-chloro-4-(dimethoxymethyl)chroman-4-yl]methanol (1.50 g, 100%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.26 (m, 1H),6.86-6.84 (m, 2H), 4.48 (s, 1H), 4.29-4.23 (m, 1H), 4.66-4.11 (m, 1H),3.98 (d, J=11.2 Hz, 1H), 3.56 (d, J=11.2 Hz, 1H), 3.48 (s, 3H), 3.36 (s,3H), 2.26-2.20 (m, 1H), 2.08-1.97 (m, 1H).

Step 9:N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(4R)-7-chloro-4-(dimethoxymethyl)chroman-4-yl]methoxy]benzenesulfonamide

To a solution of [(4R)-7-chloro-4-(dimethoxymethyl)chroman-4-yl]methanol(1.50 g, 5.5 mmol) in anhydrous THF (50 mL) was added KOBu-t (1.23 g, 11mmol). After stirring for 5 min at r.t., a solution of4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide(3.04 g, 6.6 mmol, Intermediate 2 Step 1) in THF (30 mL) was addeddropwise and the resulting mixture was stirred at r.t. for 3 h. Thereaction was quenched with saturated NH₄Cl solution (50 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with NH₄Cl (50 mL) and brine (50 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography on a silica gel column elutingwith ethyl acetate/hexane (20%) to affordN,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(4R)-7-chloro-4-(dimethoxymethyl)chroman-4-yl]methoxy]benzenesulfonamide(3.35 g, 85% yield) as a yellow semi-solid. ¹H NMR (400 MHz, CDCl₃) δ8.04 (d, J=2.4 Hz, 1H), 7.78 (dd, J=2.4, 8.8 Hz, 1H), 7.51 (d, J=8.8 Hz,1H), 7.00-6.97 (m, 5H), 6.82-6.79 (m, 2H), 6.73-6.70 (m, 4H), 4.68 (s,1H), 4.28-4.21 (m, 8H), 3.72 (s, 6H), 3.42 (s, 3H), 3.25 (s, 3H),2.31-2.25 (m, 1H), 1.97-1.84 (m, 1H).

Step 10:(R)-4-((7-chloro-4-formylchroman-4-yl)methoxy)-N,N-bis(4-methoxybenzyl)-3-nitrobenzenesulfonamide

To a solution ofN,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(4R)-7-chloro-4-(dimethoxymethyl)chroman-4-yl]methoxy]benzenesulfonamide(3.35 g, 4.7 mmol) in 1,4-Dioxane (50 mL) and water (17 mL) was addedTsOH (1.79 g, 9.39 mmol). The resulting solution was stirred at 105° C.overnight. The reaction was diluted with ethyl acetate (50 mL) andwashed with sat. NaHCO₃solution (15 mL), water (15 mL) and brine (15mL). The organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure The residue was purified by column chromatographyon a silica gel column eluting with PE:EA (2:1) to affordN,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(4R)-7-chloro-4-formyl-chroman-4-yl]methoxy]benzenesulfonamide(2.50 g, 79% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 9.51 (s,1H), 8.09 (d, J=2.4 Hz, 1H), 6.89-7.86 (m, 1H), 7.12 (d, J=9.2 Hz, 1H),7.08-7.03 (m, 5H), 6.99-6.93 (m, 2H), 6.81-6.78 (m, 4H), 4.71 (d, J=9.2Hz, 1H), 4.37-4.35 (m, 1H), 4.30-4.23 (m, 6H), 3.79 (s, 6H), 2.54-2.47(m, 1H), 2.42-2.36 (m, 1H).

Step 11:(S)-7′-chloro-N,N-bis(4-methoxybenzyl)-4,5-dihydro-2H-spiro[benzo[b][1,4]oxazepine-3,4′-chromane]-7-sulfonamide

To a solution ofN,N-bis[(4-methoxyphenyl)methyl]-3-nitro-4-[[(4R)-7-chloro-4-formyl-chroman-4-yl]methoxy]benzenesulfonamide(2.50 g, 3.75 mmol) and NH₄Cl (1.99 g, 37.4 mmol) in ethanol (30 mL) wasadded zinc (2.45 g, 37.4 mmol) and the resulting solution was stirred at80° C. under N₂ atmosphere overnight. After cooling, the mixture wasfiltered through a pad of celite. The filtrate was concentrated underreduced pressure. The residue was purified by column chromatography on asilica gel column eluting with PE:EA (2:1) to afford(3S)-7′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide(1.44 g, 58% yield) as a white solid. LC-MS calc. for C₃₃H₃₄ClN₂O₆S[M+H]⁺: m/z=621.17/623.17; Found: 621.2/623.2. ¹H NMR (400 MHz, CDCl₃) δ7.71 (d, J=8.4 Hz, 1H), 7.21-7.18 (m, 1H), 7.04-6.93 (m, 6H), 6.91 (m,1H), 6.85 (d, J=2.4 Hz, 1H), 6.78-6.75 (m, 4H), 4.23-4.10 (m, 8H), 3.78(s, 6H), 3.53 (d, J=12.8 Hz, 1H), 3.40 (d, J=12.8 Hz, 1H), 2.05-2.00 (m,1H), 1.96-1.92 (m, 1H).

Intermediate 12(3S)-7′-Chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamideand Intermediate 13(3S)-7′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide

Step 1:(3S)-7′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide

This compound was prepared using procedures analogous to those describedfor Intermediate 3 Step 1-3 using(3S)-7′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide(Intermediate 11) and [(1R,2R)-2-formylcyclobutyl]methyl acetate inStep 1. LC-MS: calc. for C₃₉H₄₂ClN₂O₇S [M+H]⁺: m/z=717.3/719.3; Found:717.4/719.2.

Step 2:(3S)-7′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamideand(3S)-7′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide

This compound was prepared using procedures analogous to those describedfor Intermediate 3 Step 4 using vinylmagnesium bromide (1.0 M solutionTHF solution). The reaction was quenched with sat. NH₄Cl solution (300mL) and extracted with (EA 300 mL×3). The organic layer was concentratedand purified by flash chromatography on a silica gel column eluting withEA/Hep (20% to 50%) to afford the two products: P1 (the earlier elutedproduct) which was assigned to(3S)-7′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide.LC-MS calc. for C₄₁H₄₆ClN₂O₇S [M+H]⁺: m/z=745.3/747.3; Found:745.5/747.4.

And P2 (the latter eluted product) was assigned to(3S)-7′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide.LC-MS calc. for C₄₁H₄₆ClN₂O₇S [M+H]⁺: m/z=745.3/747.3; Found:745.5/747.4.

Step 3:(3S)-7′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide(Intermediate 12)

This compound was prepared using procedures analogous to those describedfor Intermediate 3 Step 5 using(3S)-7′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide(P1 Step 2). LC-MS: calcd. for C₂₅H₃₀ClN₂O₅S [M+H]⁺: m/z=505.0/507.0;Found: 505.1/507.0.

Step 4:(3S)-7′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide(Intermediate 13)

This compound was prepared using procedures analogous to those describedfor Intermediate 3 Step 5 using(3S)-7′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide(P2 Step 2). LC-MS: calc. for C₂₅H₃₀ClN₂O₅S [M+H]⁺: m/z=505.0/507.0;Found: 505.1/507.0.

Intermediate 14(R)-6′-Chloro-N,N-bis(4-methoxybenzyl)-4,5-dihydro-2H-spiro[benzo[b][1,4]oxazepine-3,1′-isochroman]-7-sulfonamide

Step 1: 2-(2-bromo-5-chlorophenyl)ethanol (LGY001-54-1)

To a suspension of 2-(2-bromo-5-chloro-phenyl)acetic acid (60.0 g, 240mmol) in THF (300 mL) was added BH3-THF (760 mL, 760 mmol) at 0° C. Thereaction mixture was stirred at 25° C. for 4 h., and then quenched byMeOH (300 mL) under N₂ at 0° C. The mixture was concentrated to givecrude product which was diluted with DCM (100 mL) and washed with 1 MHCl and brine. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduce pressure to afforded2-(2-bromo-5-chloro-phenyl)ethanol (60 g, 84% yield) as a colorless oilwhich was used for the next step directly. ¹H NMR: (400 MHz, CDCl₃) δ7.46 (d, J=8.4 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 7.07 (dd, J=2.8 Hz, 8.8Hz, 1H), 3.86 (t, J=6.4 Hz, 2H), 2.97 (t, J=6.4 Hz, 2H), 1.88 (s, 1H).

Step 2: (2-bromo-5-chlorophenethoxy)(tert-butyl)dimethylsilane

tert-Butylchlorodimethylsilane (25.34 g, 168 mmol) was slowly added to asolution of imidazole (17.34 g, 254 mmol) and2-(2-bromo-5-chloro-phenyl)ethanol (60.0 g, 254 mmol) in dry DCM (400mL) at 0° C. over 30 min. After addition, the reaction mixture wasstirred at r.t. for 18 h., and treated with 5% of NaHCO₃aqueous. Themixture was extracted with EA (200 mL×3). The combined organic layerswere washed with brine (100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography on a silica gel column eluting with PE. EA (0-10%)to give 2-(2-bromo-5-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane (61g, 68% yield) as an colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d,J=8.4 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.09 (dd, J=8.4, 2.8 Hz, 1H),3.85 (t, J=6.4 Hz, 2H), 2.97 (t, J=6.4 Hz, 2H), 0.90 (s, 9H), 0.00 (s,6H).

Step 3:5-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-chlorophenyl)-2,2-dimethyl-1,3-dioxan-5-ol

To a solution of2-(2-bromo-5-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane (40.0 g,114 mmol) in THF (400 mL) was added n-BuLi (54.8 mL, 137 mmol) (2.5 M inhexane) at −78° C. dropwised, and stirred at this temperature for 30min. To the reaction mixture was added 2,2-dimethyl-1,3-dioxan-5-one(20.8 g, 160 mmol) in THF (15 mL), stirred at −78° C. to −15° C. for 4h. The mixture was quenched by sat. NH₄Cl (150 mL), and extracted withEA (150 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column eluting withPE/EA (2-10%) to give5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chloro-phenyl]-2,2-dimethyl-1,3-dioxan-5-ol(30 g, 65% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d,J=8.4 Hz, 1H), 7.33-7.18 (m, 2H), 4.84 (s, 1H), 4.18 (d, J=11.6 Hz, 2H),4.03 (d, J=11.6 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 3.24 (t, J=6.0 Hz, 2H),1.62 (s, 3H), 1.52 (s, 3H), 0.88 (s, 9H), 0.01 (s, 6H).

Step 4:5-(4-chloro-2-(2-hydroxyethyl)phenyl)-2,2-dimethyl-1,3-dioxan-5-ol(LGY001-75-1)

To a solution of5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chloro-phenyl]-2,2-dimethyl-1,3-dioxan-5-ol(30.0 g, 74.8 mmol) in THF (150 mL) was slowly added TBAF (97 mL, 97mmol) (1 M in THF) at 0° C. After addition, the mixture was stirred at25° C. for 1 h., and diluted with EtOAc (150 mL). The mixture was washedwith brine (50 mL) and H₂O (50 mL×3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with PE/EA (10-50%) to give5-(4-chloro-2-(2-hydroxyethyl)phenyl)-2,2-dimethyl-1,3-dioxan-5-ol (21g, 97% yield) as a colorless oil. TLC (PE/EA=2/1, Rf=0.2). ¹H NMR (400MHz, DMSO-d₆) δ 7.61 (d, J=8.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.22(dd, J=8.4, 2.4 Hz, 1H), 5.44 (s, 1H), 4.75 (t, J=5.0 Hz, 1H), 4.03 (d,J=11.6 Hz, 2H), 3.84 (d, J=11.6 Hz, 2H), 3.62 (dd, J=12.0, 6.8 Hz, 2H),3.04 (t, J=6.8 Hz, 2H), 1.44 (s, 3H), 1.28 (s, 3H).

Step 5: 6′-chloro-2,2-dimethylspiro[[1,3]dioxane-5,1′-isochroman](LGY001-80-1)

To a solution of5-[4-chloro-2-(2-hydroxyethyl)phenyl]-2,2-dimethyl-1,3-dioxan-5-ol (42.0g, 146 mmol) in THF (150 mL) was added Ph₃P (69.15 g, 263 mmol), andfollowed by DIAD (52.27 mL, 263.64 mmol) at 0° C. dropwise. The mixturewas stirred at 0° C. for 1 h. and 25° C. for 2 h. The reaction wasconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with PE/EA (5%) to give (27 g,68.6% yield) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (d,J=8.4 Hz, 1H), 7.29-7.25 (m, 2H), 3.92 (d, J=12.4 Hz, 2H), 3.84 (t,J=5.6 Hz, 2H), 3.77 (d, J=12.4 Hz, 2H), 2.75 (t, J=5.6 Hz, 2H), 1.51 (s,3H), 1.35 (s, 3H).

Step 6: (6-chloroisochroman-1,1-diyl)dimethanol (LGY001-82-1)

To a solution of6′-chloro-2,2-dimethyl-spiro[1,3-dioxane-5,1′-isochromane] (17.0 g, 63.2mmol) in methanol (25 mL) was added TsOH (0.6 g, 3.16 mmol) and stirredat 25° C. for 18 h. The mixture was quenched by NaHCO₃aqueous (20 mL),and extracted with EtOAc (100 mL×3). The combined organic layers werewashed with brine and water, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give(6-chloroisochroman-1,1-diyl)dimethanol (7.6 g, 52.5% yield) as a whitesolid which was used for next step directly. TLC (silica gel, PE/EA=1/1,R.f.=0.4). ¹H NMR (400 MHz, CDCl₃) δ 7.20 (dd, J=8.4, 2.4 Hz, 1H), 7.16(d, J=2.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.01 (t, J=5.6 Hz, 1H),3.91-3.83 (m, 4H), 2.84 (t, J=5.6 Hz, 1H), 2.20 (s, 2H).

Step 7: (R)-(6-chloro-1-(hydroxymethyl)isochroman-1-yl)methyl4-bromobenzoate (LGY001-98-1)

To a solution of R,R-Kang catalyst(2,6-bis((R)-5,5-dibutyl-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine)(908.93 mg, 1.53 mmol) in dry DCM (25 mL) was added Copper(II) chloride(205.79 mg, 1.53 mmol). The resulting green solution was stirred atambient temperature for 3 h. This solution was transferred via cannulato a solution of 4-bromobenzoyl chloride (5.76 g, 26.2 mmol) in dry DCM(25 mL). The resulting solution was cooled to −78° C. and light greencolored precipitation was observed in the reaction after some time. Asolution of [6-chloro-1-(hydroxymethyl)isochroman-1-yl]methanol (5.0 g,21.87 mmol)) in DCM (25 mL) was then added slowly (over 10 min.),followed by the dropwise addition of DIPEA (3.81 mL, 21.8 mmol). Theresulting mixture was stirred at −78° C. for 2 h., and quenched byKH₂PO₄ sat. aqueous solution (100 mL) and allowed to warm to ambienttemperature with vigorous stirring. The reaction was diluted with ethylacetate (400 mL) and the layers were separated. The organic phase waswashed with pH˜3 buffer (1×50 mL), saturated NaHCO₃ (2×100 mL), andbrine (100 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure The crude material was purified by flashchromatography on a silica gel column eluting with EA/PE (5-10%) to give(R)-(6-chloro-1-(hydroxymethyl)isochroman-1-yl)methyl 4-bromobenzoate(5.1 g, 56% yield). The chiral HPLC showed (e.e=93%): Chiral Column: AD,2.5 um, 3.0 mm×150 mm; Mobile phase A: Supercritical CO₂, Mobile phaseB: MeOH (with 0.1% DEA), A:B=50:50; Run time: 18 min.; DetectorWavelength: 254 nm, Instrument: Waters Acouity UPC² 0.1H NMR (400 MHz,CDCl₃) δ 7.79 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.26-7.16 (m,3H), 4.72 (d, J=12.0 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 4.13-3.96 (m,2H), 3.98-3.84 (m, 2H), 2.88-2.78 (m, 2H).

Step 8: (S)-(6-chloro-1-formylisochroman-1-yl)methyl 4-bromobenzoate(LGY001-100-1)

To a solution of (R)-(6-chloro-1-(hydroxymethyl)isochroman-1-yl)methyl4-bromobenzoate (2.6 g, 6.32 mmol) in DCM (35 mL) was added Dess-Martinperiodinane (3.48 g, 8.21 mmol) at 10° C. After addition, the coolingbath was removed. The reaction mixture was stirred for 2 h. at ambienttemperature. The reaction was then cooled to 0° C., and diluted withethyl acetate (100 mL), quenched with a 1:1 mixture of 10% Na₂S₂O₃ andsaturated NaHCO₃ (100 mL) solution and stirred at r.t. for an additional0.5 h. The aqueous phase was separated. The organic phase was washedwith brine (100 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude material was purified byflash chromatography on a silica gel column eluting with ethyl acetatein hexanes (10%) to afforded[(S)-6-chloro-1-formyl-isochroman-1-yl]methyl 4-bromobenzoate (2.00 g,77% yield) as light yellow oil. R_(f)=0.5 in 10% ethyl acetate inhexane. ¹H NMR (400 MHz, CDCl₃) δ 9.68 (s, 1H), 7.81 (d, J=8.4 Hz, 2H),7.56 (d, J=8.4 Hz, 2H), 7.26 (m, 2H), 7.21 (s, 1H), 4.85 (d, J=11.6 Hz,1H), 4.67 (d, J=11.6 Hz, 1H), 4.26-4.12 (m, 1H), 4.09 (m, 1H), 2.98-2.78(m, 2H).

Step 9: (S)-(6-chloro-1-(dimethoxymethyl)isochroman-1-yl)methanol(LGY001-91-1)

To a solution of (S)-(6-chloro-1-formylisochroman-1-yl)methyl4-bromobenzoate (700.0 mg, 1.71 mmol) in anhydrous methanol (15 mL),TsOH (16.25 mg, 0.09 mmol) and trimethyl orthoformate (217 mg, 2.05mmol) were added and the reaction mixture was refluxed for 4 h. Thereaction mixture was then concentrated to 50% volume, diluted with THF(12 mL) and added NaOH (273 mg, 6.83 mmol) in water (2 mL). Theresulting mixture was stirred at r.t. overnight, concentrated underreduced pressure. The residue was diluted with diethyl ether (50 mL).The aqueous layer was separated, and the organic layer was washed with 1N NaOH (10 mL). The combined aqueous layers were extracted with diethylether (20 mL). The combined organic layers were washed with 1 N NaOH (10mL) and brine, dried over sodium sulfate and concentrated under reducedpressure. The crude material was purified by flash chromatography on asilica gel column eluting with ethyl acetate/hexane (20%) to afford(S)-(6-chloro-1-(dimethoxymethyl)isochroman-1-yl)methanol (320 mg, 68%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J=8.5 Hz,1H), 7.18-7.03 (m, 2H), 4.16-4.13 (m, 1H), 3.96-3.93 (m, 2H), 3.70 (d,J=11.6 Hz, 1H), 3.54 (s, 3H), 3.48 (s, 3H), 2.90-2.69 (m, 2H).

Step 10:(S)-4-((6-chloro-1-(dimethoxymethyl)isochroman-1-yl)methoxy)-N,N-bis(4-methoxybenzyl)-3-nitrobenzenesulfonamide

To a solution of tert-butoxypotassium (987.47 mg, 8.8 mmol) in anhydrousTHF (3 mL) was cooled to 0° C. and a solution of(S)-(6-chloro-1-(dimethoxymethyl)isochroman-1-yl)methanol (2.0 g, 7.33mmol) in THF (5 mL) was added dropwise. After 5 min.,4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide(4390 mg, 9.53 mmol) (1 M in THF) was added dropwise via syringe and theresulting mixture was warmed to r.t. After 1 h the reaction was cooledto 0° C., quenched with saturated NH₄CI solution (10 mL) and extractedwith ethyl acetate (50 mL). The combined organic layers were washed withNH₄CI (10 mL), brine (20 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude material was purified byflash chromatography on a silica gel column eiuting with ethylacetate/PE (25%) (TLC Rf=0.5 in 30% ethyl acetate in hexane) to afford(S)-4-((6-chloro-1-(dimethoxymethyl)isochroman-1-yl)methoxy)-N,N-bis(4-methoxybenzyl)-3-nitrobenzenesulfonamide(4.2007 g, 80% yield) as a yellow semi-solid. ¹H NMR (400 MHz, CDCl₃) δ8.10 (d, J=2.4 Hz, 1H), 7.85 (dd, J=8.8, 2.4 Hz, 1H), 7.50 (d, J=8.6 Hz,1H), 7.21-7.16 (m, 2H), 7.09-7.04 (m, 5H), 6.82-6.76 (m, 4H), 4.71 (s,1H), 4.38 (s, 2H), 4.27 (s, 4H), 4.18-4.13 (m, 1H), 4.02-3.92 (m, 1H),3.79 (s, 6H), 3.54 (d, J=2.0 Hz, 3H), 3.50 (s, 3H), 2.83 (m, 2H).

Step 11:(S)-4-((6-chloro-1-formylisochroman-1-yl)methoxy)-N,N-bis(4-methoxybenzyl)-3-nitrobenzenesulfonamide

To a solution(S)-4-((6-chloro-1-(dimethoxymethyl)isochroman-1-yl)methoxy)-N,N-bis(4-methoxybenzyl)-3-nitrobenzenesulfonamide(3.5 g, 4.91 mmol) in 1,4-dioxane (30 mL) was added TsOH (2.53 g, 14.72mmol) and the suspension was heated to 110° C. for 18 h. Uponcompletion, the mixture was cooled to r.t., and concentrated underreduced pressure. The residue was dissolved in EtOAc (100 mL) and washedby NaHCO₃ (100 mL). The organic layer was concentrated to give(S)-4-((6-chloro-1-formylisochroman-1-yl)methoxy)-N,N-bis(4-methoxybenzyl)-3-nitrobenzenesulfonamide(3.2 g, 78.2% yield) which was used directly in next step. ¹H NMR (400MHz, CDCl₃) δ 9.71 (s, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.85 (dd, J=8.8, 2.4Hz, 1H), 7.26-7.45 (m, 3H), 7.10-7.03 (m, 5H), 6.81-6.77 (m, 4H),4.59-4.48 (m, 2H), 4.26 (s, 4H), 4.16-4.07 (m, 2H), 3.79 (s, 6H),3.02-2.85 (m, 2H).

Step 12:(R)-6′-chloro-N,N-bis(4-methoxybenzyl)-4,5-dihydro-2H-spiro[benzo[b][1,4]oxazepine-3,1′-isochroman]-7-sulfonamide

To a solution(S)-4-((6-chloro-1-formylisochroman-1-yl)methoxy)-N,N-bis(4-methoxybenzyl)-3-nitrobenzenesulfonamide(500 mg, 0.75 mmol) in acetic acid (8 mL) was added iron powder (3382mg, 14.9 mmol) and the suspension was heated to 40° C. for 12 h. Uponcompletion, the suspension was cooled to r.t. The solid was filtered offand the filtrate was concentrated under reduced pressure. The residuewas diluted with DCE (10 mL). To the solution was added NaHB(OAc)₃ (795mg, 3.75 mmol). The reaction mixture was stirred at r.t. for 3 h., andMeOH (10 mL) was added. The resulting mixture was stirred for 1 h., andthen concentrated under reduced pressure. The residue was purified byflash chromatograph on a silica gel column to afford(R)-6′-chloro-N,N-bis(4-methoxybenzyl)-4,5-dihydro-2H-spiro[benzo[b][1,4]oxazepine-3,1′-isochroman]-7-sulfonamide(70 mg, 14% yield). LC-MS calc. for C₃₃H₃₄ClN₂O₆S [M+H]⁺:m/z=621.18/623.18; Found: 621.1/623.0. ¹H NMR (400 MHz, CDCl₃) δ 7.62(d, J=8.4 Hz, 1H), 7.25-7.21 (m, 2H), 7.20 (d, J=2.0 Hz, 1H), 7.08 (d,J=2.4 Hz, 1H), 7.02-6.99 (m, 5H), 6.80-6.76 (m, 4H), 4.38 (dd, J=41.2,12.6 Hz, 2H), 4.24 (s, 4H), 3.99 (t, J=5.6 Hz, 2H), 3.78-3.75 (m, 7H),3.51 (d, J=14.0 Hz, 1H), 2.85 (t, J=5.2 Hz, 2H).

Intermediate 15(3R)-6′-Chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamideand Intermediate 16(3R)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide

Step 1:(3R)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide

This compound was prepared using procedures analogous to those describedfor Intermediate 3 Step 1-3 using(R)-6′-chloro-N,N-bis(4-methoxybenzyl)-4,5-dihydro-2H-spiro[benzo[b][1,4]oxazepine-3,1′-isochroman]-7-sulfonamide(Intermediate 14) and [(1R,2R)-2-formylcyclobutyl]methyl acetate inStep 1. LC-MS: calc. for C₃₉H₄₂ClN₂O₇S [M+H]⁺: m/z=717.3/719.3; Found:717.3/719.3.

Step 2:(3R)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamideand(3R)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide

This compound was prepared using procedures analogous to those describedfor Intermediate 3 Step 4 using vinylmagnesium bromide (1.0 M solutionTHF solution). The reaction was quenched with sat. NH₄Cl solution (300mL) and extracted with (EA 300 mL×3). The organic layer was concentratedand purified by flash chromatography on a silica gel column eluting withEA/Hep (20% to 50%) to afford the two products: P1 (the earlier elutedproduct) which was assigned to(3R)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide.LC-MS calc. for C₄₁H₄₆ClN₂O₇S [M+H]⁺: m/z=745.3/747.3; Found:745.5/747.4.

And P2 (the latter eluted product) was assigned to(3R)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide.LC-MS calc. for C₄₁H₄₆ClN₂O₇S [M+H]⁺: m/z=745.3/747.3; Found:745.5/747.4.

Step 3:(3R)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide(Intermediate 15)

This compound was prepared using procedures analogous to those describedfor Intermediate 3 Step 5 using(3R)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide(P1 Step 2). LC-MS: calcd. for C₂₅H₃₀ClN₂O₅S [M+H]⁺: m/z=505.0/507.0;Found: 505.1/507.0.

Step 4:(3R)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide(Intermediate 16)

This compound was prepared using procedures analogous to those describedfor Intermediate 3 Step 5 using(3R)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide(P2 Step 2). LC-MS: calc. for C₂₅H₃₀ClN₂O₅S [M+H]⁺: m/z=505.0/507.0;Found: 505.1/507.0.

Example 1N-[6′-Chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide

Step 1:6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

A 20 mL vial with septum under N2 containing a solution of ˜80% pure6′-chlorospiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 1, 400 mg, 0.84 mmol) in DCM (9 mL) and2,2,2-trifluoroacetic acid (TFA) (1.5 mL, 19.6 mmol) was charged withcyclobutanecarboxaldehyde (very impure, 262 μL, 3.36 mmol). The solutionwas stirred at RT for 30 min. The reaction vessel was then placed at 0°C. in an ice-water bath, and charged with sodium borohydride (100 mg,2.64 mmol) in small portions over 2 min. The reaction was stirred at 0°C. for 1 h. The reaction was quenched by dumping it into sat.NaHCO₃ (20mL, caution:gas evolution), diluting with water (30 mL) and extractingwith EtOAc (60 mL). The organic layer was washed with water (20 mL) andsat. NaHCO₃ (20 mL), brine (30 mL), dried over Na₂SO₄, and filtered. Thefiltrate was concentrated to afford a yellow gum, then turned into ayellow/white solid by repeated concentration after dissolving in DCM andtriturating with hexanes. Solids were mostly dissolved in hot DCM (˜10mL), then charged with hexanes until a cloudy color appeared. Theresulting suspension was let cool to RT, then cooled to 0° C. After 2 h,a white/grey precipitate formed. The supernatant was decanted, and theprecipitate was washed twice more with DCM/hexanes (2×2 mL, 2:1 ratio).The precipitate was dried under reduced pressure to yield6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(105 mg, 27.9% yield) as a grey solid.

The remaining filtrates were combined, dry loaded on Celite, andpurified by FCC (40 g SiO₂, 0→50% EtOAc in hexanes). Fractionscontaining pure desired product by TLC were combined and concentratedunder reduced pressure and heat (−50° C.) to yield6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(93.8 mg, 24.8% yield) as a white solid. Combined yield of 52.7%.R_(f)=0.28 (2:1 hexanes:EtOAc); LCMS calculated for C₂₃H₂₈ClN₂O₃S(M+H)⁺: m/z=447.15/449.15; found: 447.0/449.0; ¹H NMR (500 MHz, CDCl₃) δ7.67 (d, J=8.5 Hz, 1H), 7.24 (dd, J=2.2, 8.3 Hz, 1H), 7.19-7.14 (m, 2H),7.09 (d, J=2.3 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.74 (s, 2H), 4.11 (ABq,2H), 3.60 (dd, J=1.2, 14.4 Hz, 1H), 3.40-3.26 (m, 3H), 2.84-2.74 (m,2H), 2.74-2.64 (m, 1H), 2.14-2.04 (m, 2H), 1.97-1.76 (m, 7H), 1.61-1.53(m, 1H).

Step 2:N-[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide

A 2 mL microwave vial with septum containing a mixture of solid6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(18. mg, 0.04 mmol), 4-(dimethylamino)pyridine (0.74 mg, 0.01 mmol), andDCM (1 mL) under N2 was charged with acetyl chloride (5.75 uL, 0.08mmol), followed by N,N-Diisopropylethylamine (17.54 uL, 0.10 mmol) atr.t. (white vapors appeared). The mixture was shaken then stirredvigorously at 45° C. for 30 min, and shaken occasionally until allsolids were dissolved. The reaction solution was quenched by addition ofsat. NH₄Cl (3 mL). The mixture was extracted with DCM (3 mL), washedwith water (2 mL) and sat. NH₄Cl (2 mL), brine (4 mL), dried overNa₂SO₄, and filtered. The filtrate was concentrated under reducedpressure. The residue was purified by FCC (12 g SiO₂, 0→35% EtOAc inhexanes, wet-loaded in DCM). Fractions containing pure product werecombined, and concentrated under reduced pressure and heat (−75° C.) toyield 98% pureN-[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide(14.2 mg, 70.6% yield) as a white solid after scratching. LCMScalculated for C₂₅H₃₀ClN₄O₄S (M+H)⁺: m/z=489.15/491.15; found:489.0/491.0. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (s, 1H), 7.67 (d, J=8.5 Hz,1H), 7.32 (dd, J=2.2, 8.3 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 7.17 (dd,J=2.3, 8.5 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.13(s, 2H), 3.60 (d, J=14.7 Hz, 1H), 3.39-3.29 (m, 3H), 2.82-2.74 (m, 2H),2.70 (dt, J=7.3, 14.0 Hz, 1H), 2.17-2.06 (m, 5H), 1.96-1.71 (m, 8H).

Example 2N-[6′-Chloro-5-(cyclopropylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide

Step 1:6′-chloro-5-(cyclopropylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of6′-chlorospiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 1, 60. mg, 0.16 mmol) in TFA (0.18 mL, 2.38 mmol) and DCM(1 mL) was added cyclopropylcarboxaldehyde (16.65 mg, 0.24 mmol). Themixture was stirred at r.t. for 15 min., then the mixture was cooled byice-water bath, and sodium borohydride (15 mg, 0.40 mmol) was addedslowly (over 15 min). The mixture was stirred at 0° C. for 1 h., thenthe volatiles were removed under reduced pressure. The residue wasdiluted with AcOEt (5 mL), and washed with sat. NaHCO₃solution (2 mL×2),and brine. The organics was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to afford the crude product6′-chloro-5-(cyclopropylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(49 mg, 71%) was directly used in next step reaction without furtherpurification. LCMS calculated for C₂₂H₂₆ClN₂O₃S (M+H)⁺:m/z=433.13/435.12; found: 433.0/435.0.

Step 2:N-[6′-chloro-5-(cyclopropylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide

To a mixture of6′-chloro-5-(cyclopropylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(21 mg, 0.05 mmol), acetic acid (0.01 mL, 0.10 mmol) and4-(dimethylamino)pyridine (12.2 mg, 0.10 mmol) in DCM (2 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.1 mg,0.10 mmol) at r.t. The mixture was stirred at r.t. overnight. Themixture was concentrated under reduced pressure. The residue waspurified by FC on a silica gel column eluting with EtOAc/Hex (0-60%)(both contains 0.3% AcOH) to afford the desired product as white solid.LCMS calculated for C₂₄H₂₈ClN₂O₄S (M+H)⁺: m/z=475.14/476.14; found:475.0/477.0. ¹H NMR (500 MHz, DMSO-d₆) δ 11.90 (s, 1H), 7.67 (d, J=8.5Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.24 (dd, J=2.4, 8.5 Hz, 1H), 7.19 (dd,J=2.2, 8.3 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 4.09(s, 2H), 3.56 (d, J=14.4 Hz, 1H), 3.45 (d, J=14.4 Hz, 1H), 3.28 (s, 1H),3.21 (dd, J=5.9, 14.8 Hz, 1H), 3.09 (dd, J=6.7, 14.8 Hz, 1H), 2.79-2.64(m, 2H), 2.04-1.91 (m, 1H), 1.90 (s, 3H), 1.76 (d, J=14.5 Hz, 2H), 1.48(m, 1H), 1.09-0.99 (m, 1H), 0.51 (dq, J=2.1, 8.2 Hz, 2H), 0.33-0.28 (m,1H), 0.27-0.21 (m, 1H).

Example 3N-[6′-Chloro-5-(cyclohexylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide

This compound was prepared using procedures analogous to those describedfor Example 2 using cyclohexanecarboxaldehyde to replacecyclopropylcarboxaldehyde in Step I. LCMS calculated for C₂₇H₃₄ClN₂O₄S(M+H)⁺: m/z=517.18/519.18; found: 517.1/519.1. ¹H NMR (500 MHz, DMSO-d₆)δ 11.92 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.23 (dt, J=2.6, 5.8 Hz, 2H),7.19-7.13 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 4.08 (q, J=12.2 Hz, 2H), 3.61(d, J=14.4 Hz, 1H), 3.34 (d, J=14.2 Hz, 1H), 3.18 (dd, J=6.4, 14.8 Hz,1H), 3.07 (dd, J=7.4, 14.8 Hz, 1H), 2.81-2.64 (m, 2H), 1.99-1.92 (m,1H), 1.91 (s, 3H), 1.79 (m, 3H), 1.75-1.63 (m, 4H), 1.63-1.56 (m, 1H),1.52 (m, 1H), 1.13 (m, 3H), 0.96 (m, 2H).

Example 4N-(5-Benzyl-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl)sulfonylacetamide

This compound was prepared using procedures analogous to those describedfor Example 2 using benzaldehyde to replace cyclopropylcarboxaldehyde inStep I. LCMS calculated for C₂₇H₂₈ClN₂O₄S (M+H)⁺: m/z=511.14/513.14;found: 511.0/513.0. ¹H NMR (500 MHz, DMSO-d₆) δ 11.77 (s, 1H), 7.70 (d,J=8.6 Hz, 1H), 7.31 (dd, J=6.8, 8.5 Hz, 2H), 7.27-7.17 (m, 5H), 7.14 (d,J=2.3 Hz, 1H), 7.09-7.01 (m, 2H), 4.64-4.53 (m, 2H), 4.26-4.14 (m, 2H),3.75 (d, J=14.5 Hz, 1H), 3.41 (d, J=14.4 Hz, 1H), 2.72-2.64 (m, 2H),1.95 (m, 1H), 1.77 (s, 3H), 1.66 (m, 2H), 1.51 (t, J=12.3 Hz, 1H), 1.22(m, 2H).

Example 5N-[6′-Chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-phenyl-acetamide

A 4 mL vial with septum containing a suspension of6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Example 1 Step 1, 40 mg, 0.09 mmol) and 4-(dimethylamino)pyridine (1.5mg, 0.01 mmol) in DCM (2 mL) and N,N-diisopropylethylamine (40 μL, 0.23mmol) under N₂ was charged with phenylacetyl chloride (18 μL, 0.14mmol). The vial was heated at 40° C. for 30 min. The reaction mixturewas charged with additional phenylacetyl chloride (23 μL, 0.17 mmol) andN,N-diisopropylethylamine (60 uL, 0.34 mmol), and heated at 40° C. for 1h. The reaction mixture was diluted with EtOAc (40 mL), washed with sat.NH₄Cl (20 mL), water (20 mL) and sat. NH₄Cl (20 mL), and brine (30 mL).The organic layer was dried over Na₂SO₄, filtered, concentrated underreduced pressure, and purified by FCC (30 g C18, 10→100% MeCN in water,wet-loaded in DMSO). The fraction containing pure desired product waslyophilized, then further dried under reduced pressure and heat (60° C.)to yieldN-[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-phenyl-acetamide(21.5 mg, 97% purity, 41% yield) as a white solid. LCMS calculated forC₃₁H₃₄ClN₂O₄S (M+H)⁺: m/z=565.19/567.19; found: 565.2/567.1. ¹H NMR (500MHz, CDCl₃) δ 7.76 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.41-7.30 (m, 3H),7.30-7.26 (m, 2H), 7.20-7.14 (m, 3H), 7.09 (d, J=2.3 Hz, 1H), 6.95 (d,J=8.8 Hz, 1H), 4.13 (s, 2H), 3.63 (s, 2H), 3.59 (d, J=14.3 Hz, 1H),3.38-3.26 (m, 3H), 2.83-2.71 (m, 2H), 2.68 (p, J=7.2 Hz, 1H), 2.13-2.04(m, 2H), 1.97-1.71 (m, 8H).

Example 6N-[6′-Chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-propanamide

This compound was prepared using procedures analogous to those describedfor Example 5 using isobutyryl chloride to replace phenylacetylchloride. The product was purified by FCC (12 g SiO₂, 0→20% EtOAc inhexanes with 0.3% AcOH, wet-loaded in DCM to affordN-[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-propanamideas a white solid. R_(f)=0.40 (2:1 hexanes:EtOAc). LCMS calculated forC₂₇H₃₄ClN₂O₄S (M+H)⁺: m/z=517.19/517.19; found: 517.1/519.1. ¹H NMR (500MHz, CDCl₃) δ 7.91 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.33 (dq, J=2.2, 4.4Hz, 2H), 7.17 (dd, J=2.4, 8.5 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.98-6.95(m, 1H), 4.13 (s, 2H), 3.60 (d, J=14.3 Hz, 1H), 3.39-3.29 (m, 3H),2.82-2.66 (m, 3H), 2.43 (hept, J=6.9 Hz, 1H), 2.16-2.06 (m, 2H),1.97-1.73 (m, 8H), 1.16 (d, J=6.9 Hz, 6H).

Example 74-Chloro-N-[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-benzamide

This compound was prepared using procedures analogous to those describedfor Example 5 using 4-chlorobenzoyl chloride to replace phenylacetylchloride. The product was purified by FCC (12 g SiO₂, 0→20% EtOAc inhexanes with 0.3% AcOH, wet-loaded in DCM to afford4-chloro-N-[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-benzamideas a white solid. R_(f)=0.25 (2:1 hexanes:EtOAc); LCMS calculated forC₃₀H₃₁Cl2N204S (M+H)⁺: m/z=585.14/587.13; found: 585.1/587.1; ¹H NMR(500 MHz, CDCl₃) δ 8.72 (s, 1H), 7.74 (dt, J=2.0, 2.4, 8.6 Hz, 2H), 7.66(d, J=8.5 Hz, 1H), 7.48-7.39 (m, 4H), 7.16 (dd, J=2.3, 8.5 Hz, 1H), 7.09(d, J=2.3 Hz, 1H), 7.01-6.96 (m, 1H), 4.13 (s, 2H), 3.60 (d, J=14.4 Hz,1H), 3.42-3.29 (m, 3H), 2.74 (dq, J=5.5, 6.1, 17.8 Hz, 3H), 2.16-2.06(m, 2H), 1.98-1.70 (m, 8H).

Example 8N-[6′-Chloro-5-[[rac-(2S,6R)-2,6-dimethyltetrahydropyran-4-yl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide

This compound was prepared using procedures analogous to those describedfor Example 2 using(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-carbaldehyde to replacecyclopropylcarboxaldehyde in Step I. LCMS calculated for C₂₈H₃₆ClN₂O₅S(M+H)⁺: m/z=547.2/549.19; found: 547.2/549.1. ¹H NMR (500 MHz, DMSO-d₆)δ 11.91 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.24 (dd, J=2.2, 9.9 Hz, 2H),7.17 (d, J=2.4 Hz, 1H), 7.15 (dd, J=2.1, 8.3 Hz, 1H), 7.00 (d, J=8.3 Hz,1H), 4.12-4.04 (m, 2H), 3.64 (d, J=14.4 Hz, 1H), 3.30 (m, 2H) overlapwith water signal, 3.16 (qd, J=6.8, 14.8 Hz, 2H), 2.81-2.65 (m, 2H),2.13 (s, 1H), 2.02-1.92 (m, 2H), 1.90 (s, 3H), 1.85-1.73 (m, 2H), 1.62(t, J=10.6 Hz, 2H), 1.54-1.40 (m, 2H), 1.05 (dd, J=4.4, 6.2 Hz, 6H),0.90-0.77 (m, 3H).

Example 9N-[6′-Chloro-5-[(1-methylpyrazol-4-yl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide

This compound was prepared using procedures analogous to those describedfor Example 2 using 1-methyl-1H-pyrazole-4carboxaldehyde to replacecyclopropylcarboxaldehyde in Step I. LCMS calculated for C₂₅H₂₈ClN₄O₄S(M+H)⁺: m/z=515.14/517.14; found: 515.2.0/517.1. ¹H NMR (500 MHz,DMSO-d₆) δ 11.90 (s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.65 (s, 1H), 7.38 (s,1H), 7.33 (d, J=2.2 Hz, 1H), 7.23 (dd, J=2.4, 8.6 Hz, 1H), 7.20-7.14 (m,2H), 7.00 (d, J=8.3 Hz, 1H), 4.32 (s, 2H), 4.13 (s, 2H), 3.74 (s, 3H),3.49 (d, J=14.1 Hz, 1H), 3.35 (d, J=14.2 Hz, 1H), 2.69 (d, J=16.0 Hz,2H), 2.04-1.94 (m, 2H), 1.87 (s, 3H), 1.48 (m, 2H).

Example 10N-[5-[(1-Allylpyrazol-4-yl)methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylhex-5-enamide

Step 1:5-[(1-allylpyrazol-4-yl)methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

This compound was prepared using procedures analogous to those describedfor Example 2 using 1-allylpyrazole-4-carbaldehyde to replacecyclopropylcarboxaldehyde in Step I. LCMS calculated for C₂₅H₂₈ClN₄O₃S(M+H)⁺: m/z=499.15/501.15; found: 499.1/501.0. ¹H NMR (500 MHz, DMSO-d₆)δ 7.66 (t, J=4.3 Hz, 2H), 7.42 (s, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.23(dd, J=2.4, 8.5 Hz, 1H), 7.19-7.14 (m, 3H), 7.11 (dd, J=2.1, 8.3 Hz,1H), 6.97 (d, J=8.2 Hz, 1H), 5.94 (ddt, J=5.7, 10.1, 17.2 Hz, 1H),5.16-5.02 (m, 2H), 4.66 (dt, J=1.6, 5.7 Hz, 2H), 4.39-4.28 (m, 2H), 4.08(s, 2H), 3.47 (d, J=14.2 Hz, 1H), 3.34 (d, J=15.4 Hz, 1H), 2.69 (dt,J=5.7, 10.1 Hz, 2H), 2.02-1.94 (m, 2H), 1.92-1.84 (m, 1H), 1.67 (d,J=29.4 Hz, 2H), 1.52-1.40 (m, 2H), 1.27 (d, J=13.9 Hz, 2H), 1.16 (t,J=7.3 Hz, 1H), 0.84 (t, J=6.8 Hz, 1H).

Step 2:N-[5-[(1-allylpyrazol-4-yl)methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylhex-5-enamide

This compound was prepared using procedures analogous to those describedfor Example 2 using 5-hexenoic acid to replace acetic acid in Step 2.LCMS calculated for C₃₁H₃₆ClN₄₀₄S (M+H)⁺: m/z=595.21/597.20; found:595.3/597.2. ¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (s, 1H), 7.69 (s, 1H),7.67 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J=2.2 Hz, 1H), 7.23 (dd,J=2.3, 8.5 Hz, 1H), 7.18 (dd, J=2.2, 8.2 Hz, 1H), 7.16 (d, J=2.4 Hz,1H), 7.01 (d, J=8.3 Hz, 1H), 5.94 (ddt, J=5.7, 10.2, 17.1 Hz, 1H), 5.71(ddt, J=6.5, 10.1, 16.9 Hz, 1H), 5.12 (dq, J=1.5, 10.2 Hz, 1H), 5.05(dq, J=1.6, 17.0 Hz, 1H), 4.97-4.88 (m, 2H), 4.65 (dt, J=1.6, 5.8 Hz,2H), 4.33 (s, 2H), 4.12 (s, 2H), 3.49 (d, J=14.3 Hz, 1H), 3.35 (d,J=14.3 Hz, 1H), 2.69 (m, 2H), 2.17 (t, J=7.4 Hz, 2H), 2.03-1.94 (m, 2H),1.94-1.83 (m, 2H), 1.50 (p, J=7.4 Hz, 4H).

Example 11(4′Z,5′E)-6-Chloro-3,4-dihydro-2H-spiro[naphthalene-1,3′-13-thia-12-aza-1(5,7)-benzo[b][1,4]oxazepina-3(4,1)-pyrazolacyclotridecaphanen]-5′-en-11′-one13′,13′-dioxide and(4′Z,5′Z)-6-chloro-3,4-dihydro-2H-spiro[naphthalene-1,3′-13-thia-12-aza-1(5,7)-benzo[b][1,4]oxazepina-3(4,1)-pyrazolacyclotridecaphanen]-5′-en-11′-one13′,13′-dioxide

A solution ofN-[5-[(1-allylpyrazol-4-yl)methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylhex-5-enamide(Example 10, Step 2, 42 mg, 0.07 mmol) in toluene (50 mL) was evacuatedand re-charged with nitrogen for three cycles. To the solution was added(1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI)chloride (Hoveyda-Grubbs II, 8.84 mg, 0.01 mmol) in toluene (5 mL). Themixture was then heated at 105° C. for 2 h. Additional Hoveyda-Grubbs II(8.84 mg, 0.01 mmol) was added. The system was evacuated and re-chargedwith nitrogen for three cycles. The mixture was heated at 105° C.overnight. The mixture was concentrated under reduced pressure. Theresidue was purified by FC on a silica gel column eluting with EtOAc/Hex(0-60%) (both contains 0.1% AcOH). The desired fractions were collectedand concentrated under reduced pressure. The residue was furtherpurified by RP FC on C18 eluting with MeCN/water (10-80%) (both contains0.2% AcOH) to afford the desired product as slight brown solid whichcontained 1 eq. AcOH. Based on 1H NMR spectrum, the ratio of the cis-and trans-isomers is about 1:4. Some signals from the cis-isomer couldnot be distinguished and overlaps with those for the trans-isomer. LCMScalculated for C₂₉H₃₂ClN₄O₄S (M+H)⁺: m/z=567.18/569.17; found:567.1/569.1. ¹H NMR (500 MHz, Methanol-d4) δ 7.78 (d, J=8.6 Hz, 1H),7.46 (d, J=13.9 Hz, 2H), 7.32 (dd, J=2.2, 8.3 Hz, 1H), 7.18 (dd, J=2.4,8.5 Hz, 1H), 7.11 (dd, J=2.3, 5.0 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 5.51(dt, J=6.2, 14.9 Hz, 0.81H for the 1H in trans-isomer), 5.42 (dt, J=6.9,14.9 Hz, 0.81H for the 1H in trans-isomer), 5.35 (tt, J=5.0, 1.5 Hz,0.48H for the 2H in cis-isomer) 4.62-4.56 (m, 2H from trans and 4H fromcis), 4.51 (d, J=4.7 Hz, 2H), 4.23 (d, J=4.2 Hz, 2H), 3.79-3.70 (m, 1H),3.46 (d, J=14.6 Hz, 1H), 2.78 (d, J=5.8 Hz, 2H, overlaps with 2H forcis-isomer), 2.21-2.16 (m, 2H, overlaps with 2H for cis-isomer), 2.03(m, 2H, overlaps with 2H for cis-isomer), 1.97 (s, 2H, AcOH signal),1.91-1.85 (m, 2H), 1.68-1.57 (m, 4H).

Example 12N-[(3S)-6′-Chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide

Step 1:(3S)-6′-chloro-5-(cyclobutylmethyl)-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution ofrac-(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 2, 46 mg, 0.07 mmol) in TFA (0.06 mL, 0.74 mmol) and DCM(2 mL) was added cyclobutanecarboxaldehyde (12.5 mg, 0.15 mmol) Themixture was stirred at r.t. for 15 min., then the mixture was cooled byice-water bath, and sodium borohydride (8.43 mg, 0.22 mmol) was addedslowly (over 15 min). The mixture was stirred at 0° C. for 1 h., thenthe volatile was removed under reduced pressure. The residue was dilutedwith AcOEt (5 mL) and washed with sat. NaHCO₃solution (2 mL×2), andbrine. The organics was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by FC on a silica gelcolumn with EtOAc in hexane (0-50%) to afford the desired product(3S)-6′-chloro-5-(cyclobutylmethyl)-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide.LCMS calculated for C₃₉H₄₄ClN₂O₅S (M+H)⁺: m/z=687.26/689.26; found:688.7.2/689.2.

Step 2:(3S)-6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of(3S)-6′-chloro-5-(cyclobutylmethyl)-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(48. mg, 0.07 mmol) in DCM (1 mL) was added TFA (0.8 mL, 10.4 mmol). Themixture was stirred at r.t. overnight. and diluted with DCM (5 mL) andcarefully neutralized with 7.5% NaHCO₃solution to about pH 8. Theorganic layer was separated. The aqueous layer was extracted with DCM (3mL). The combined organic layers were washed with 7.5% NaHCO₃solution (2mL), and water (2 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to afford(3S)-6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamidewhich was directly used in next step reaction without furtherpurification. LCMS calculated for C₂₃H₂₈ClN₂O₃S (M+H)⁺:m/z=447.14/449.14; found: 447.0/449.0.

Step 3:N-[(3S)-6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylacetamide

To a mixture of(3S)-6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(15 mg, 0.03 mmol), acetic acid (0.5 mL, 0.07 mmol) and4-(dimethylamino)pyridine (8.2 mg, 0.07 mmol) in DCM (1 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.8 mg,0.07 mmol) at r.t. The mixture was stirred at r.t. for 1 h. The mixturewas concentrated under reduced pressure. The residue was purified by FCon a silica gel column eluting with EtOAc/Hex (0-50%). The desiredfractions were collected and concentrated under reduced pressure. Theresidue was diluted with MeCN and water, and was lyophilized to affordthe desired product as white solid. LCMS calculated for C₂₅H₃₀ClN₄O₄S(M+H)⁺: m/z=489.15/491.15; found: 489.1/491.1. ¹H NMR (500 MHz, DMSO-d₆)δ 11.90 (s, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.23 (dd, J=2.4, 8.5 Hz, 1H),7.20-7.15 (m, 3H), 7.03-6.98 (m, 1H), 4.07 (s, 2H), 3.52 (d, J=14.3 Hz,1H), 3.23-3.36 (m, 3H, overlap with water), 2.80-2.58 (m, 3H), 2.08-1.95(m, 2H), 1.92 (s, 3H), 1.91-1.84 (m, 1H), 1.77 (m, 6H), 1.51 m, 1H).

Example 13N-[(3S)-6′-Chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcyclopentanecarboxamide

To a mixture of(3S)-6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(15 mg, 0.03 mmol), 4-(dimethylamino)pyridine (8.2 mg, 0.07 mmol) andN,N-Diisopropylethylamine (0.01 mL, 0.07 mmol) in DCM (1 mL) was addedcyclopentanecarbonyl chloride (6.67 mg, 0.05 mmol) at r.t. The mixturewas stirred at r.t. for 2 h. The mixture was concentrated under reducedpressure. The residue was purified by FCC on a silica gel column elutingwith EtOAc/Hex (0-50%). The desired fractions were collected andconcentrated under reduced pressure. The residue was diluted with MeCNand water and was lyophilized to afford the desired product as whitesolid. LCMS calculated for C₂₉H₃₆ClN₄O₃S (M+H)⁺: m/z=543.2/545.2; found:543.1/545.1. ¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (s, 1H), 7.63 (d, J=8.5Hz, 1H), 7.23 (dd, J=2.4, 8.5 Hz, 1H), 7.19-7.13 (m, 3H), 6.98 (d, J=8.7Hz, 1H), 4.06 (s, 2H), 3.51 (d, J=14.3 Hz, 1H), 3.29-3.21 (m, 3H),2.81-2.57 (m, 4H), 2.00 (d, J=6.9 Hz, 2H), 1.90 (d, J=13.9 Hz, 1H),1.84-1.68 (m, 8H), 1.50 (d, J=29.6 Hz, 7H).

Example 14 BenzylN-[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamate

To a mixture of6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(15.0 mg, 0.03 mmol), Benzyl chloroformate (8.2 mg, 0.07 mmol) andN,N-Diisopropylethylamine (0.01 mL, 0.07 mmol) in DCM (1 mL) was addedBenzyl chloroformate (6.67 mg, 0.04 mmol) at r.t. The mixture wasstirred at r.t. for 2 h. The mixture was concentrated under reducedpressure. The residue was purified by FC on a silica gel column elutingwith EtOAc/Hex (0-50%). The desired fractions were collected andconcentrated under reduced pressure. The residue was diluted with MeCNand water, and was lyophilized to afford the desired product as whitesolid. LCMS calculated for C₃₁H₃₄ClN₂O₅S (M+H)⁺: m/z=581.18/583.18;found: 581.3/583.3. ¹H NMR (500 MHz, Acetonitrile-d₃) δ 9.05 (sbr, 1H),7.72 (d, J=8.5 Hz, 1H), 7.41-7.32 (m, 3H), 7.32-7.27 (m, 2H), 7.27-7.16(m, 4H), 6.98 (d, J=8.3 Hz, 1H), 5.12 (s, 2H), 4.14 (s, 2H), 3.64-3.56(m, 1H), 3.39-3.32 (m, 2H), 3.28 (dd, J=6.1, 14.9 Hz, 1H), 2.86-2.73 (m,2H), 2.66 (p, J=7.3 Hz, 1H), 2.09-2.02 (m, 3H), 1.92-1.75 (m, 6H), 1.58m, 1H).

Example 152-(1,5-Dimethylpyrazol-3-yl)-N-[(3S)-6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-acetamide

This compound was prepared using procedures analogous to those describedfor Example 12 using 2-(1,5-dimethylpyrazol-3-yl)acetic acid to replaceacetic acid in Step 3. LCMS calculated for C₃₀H₃₆ClN₄O₄S (M+H)⁺:m/z=583.21/585.21; found: 583.2/585.2. ¹H NMR (500 MHz, Chloroform-d) δ7.67 (d, J=8.5 Hz, 1H), 7.38-7.32 (m, 2H), 7.17 (dd, J=2.3, 8.5 Hz, 1H),7.09 (d, J=2.3 Hz, 1H), 6.95 (d, J=8.9 Hz, 1H), 5.95 (s, 1H), 4.12 (s,2H), 3.81 (d, J=8.3 Hz, 3H), 3.61 (s, 2H), 3.38-3.30 (m, 2H), 2.80-2.65(m, 2H), 2.33-2.20 (m, 5H), 2.16-2.05 (m, 3H), 1.99-1.71 (m, 8H).

Example 16N-[(3S)-6′-Chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-thiazol-2-yl-acetamide

This compound was prepared using procedures analogous to those describedfor Example 12 using 2-(4-thiazolyl)acetic acid to replace acetic acidin Step 3. LCMS calculated for C₂₈H₃₁ClN₃O₄S 2 (M+H)⁺:m/z=571.14/573.14; found: 571.2/573.2. ¹H NMR (500 MHz, DMSO-d₆) δ 12.33(s, 1H), 9.00 (d, J=2.0 Hz, 1H), 7.68-7.61 (m, 2H), 7.50-7.39 (m, 2H),7.24 (dd, J=2.4, 8.5 Hz, 1H), 7.21-7.14 (m, 2H), 6.98 (d, J=8.8 Hz, 1H),4.06 (s, 2H), 3.51 (d, J=14.3 Hz, 1H), 2.82-2.58 (m, 4H), 2.06-1.67 (m,12H), 1.52 (dd, J=7.0, 14.2 Hz, 1H).

Example 172-(6-Methyl-3-pyridyl)-N-[(3S)-6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-acetamide

This compound was prepared using procedures analogous to those describedfor Example 12 using 2-(6-methylpyridin-3-yl)acetic acid to replaceacetic acid in Step 3. LCMS calculated for C₃₁H₃₅ClN₃O₄S (M+H)⁺:m/z=580.2/582.20; found: 580.3/582.3. ¹H NMR (500 MHz, DMSO-d₆) δ 12.33(s, 1H), 8.51 (s, 1H), 8.00 (s, 1H), 7.63 (d, J=8.5 Hz, 2H), 7.29-7.15(m, 4H), 7.01 (d, J=8.2 Hz, 1H), 4.11-4.03 (m, 2H), 3.77 (s, 2H), 3.51(d, J=14.3 Hz, 1H), 3.35-3.20 (m, 3H), 2.82-2.67 (m, 2H), 2.58 (s, 3H),2.04-1.66 (m, 11H), 1.50 (dd, J=5.5, 12.2 Hz, 1H).

Example 18(3R,6R,24S)-6′-Chloro-17,17-dioxo-spiro[8,22-dioxa-17λ{circumflex over( )}6-thia-1,16-diazapentacyclo[16.7.2.1{circumflex over( )}9,13.0{circumflex over ( )}3,6.0{circumflex over( )}21,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one

Step 1:[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylacetate

To a solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 2, 1.20 g, 1.94 mmol) and[(1R,2R)-2-formylcyclobutyl]methyl acetate (0.333 g, 2.13 mmol) in DCM(25 mL) was added 2,2,2-trifluoroacetic acid; TFA (1.2 mL, 15.68 mmol, 8eq.). The mixture was stirred for 5 min., and then cooled with ice-waterbath. To the cooled solution was added sodium borohydride (146.64 mg,3.88 mmol) in small portion-wise over 15 min. The mixture was stirred at0° C. for 1.5 h. and was quenched by addition of methanol (1 mL). Thereaction mixture was then carefully neutralized with 7.5% NaHCO₃ aq.solution to about pH 8. The organic layer was separated and washed withwater, dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford the desired crude product (1.63 g, 90% purity)without further purification. LCMS: m/z=781.3 (M+Na)*.

Step 2:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylacetate (1635.0 mg, 1.94 mmol, 90% pure) in methanol (5 mL) and THF (5mL) was added a solution of lithium hydroxide (100 mg, 4.0 mmol) inwater (5 mL). The mixture was stirred at r.t overnight. The volatileswere removed under reduced pressure. The residue was neutralized with 1N HCl aqueous solution to about pH 7. The mixture was extracted withethyl acetate (3×5 mL). The combined organic layers were washed withwater and brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column with ethyl acetate in hexane (0-50%) to afford thedesired product (1.21 g, 87%).

Step 3: methyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]acetate

A 4 mL vial with septum containing triphenylphosphine (36.0 mg, 0.14mmol) and vacuum-dried(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(60.9 mg, 0.08 mmol) was charged with 3-hydroxyphenylacetic acid methylester (13.5 uL, 0.09 mmol) followed by diisopropyl azodicarboxylate(24.0 μL, 0.12 mmol) dropwise over 1 min at r.t. The reaction mixturewas stirred at r.t. for 2 h. The vial was then charged with additionaltriphenylphosphine (16.5 mg, 0.06 mmol), diisopropyl azodicarboxylate(15.0 μL, 0.08 mmol), and 3-hydroxyphenylacetic acid methyl ester (6.0μL, 0.04 mmol). The solution was stirred at r.t. for an additional 1 h.,then quenched with 2 drops water. The solution was dried under reducedpressure and purified by FCC (12 g SiO₂, 0→35% EtOAc in hexanes,wet-loaded in DCM). Fractions containing desired product were combinedand concentrated under reduced pressure and heat (˜100° C.) to yieldmethyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]acetate(53.6 mg, 0.0619 mmol, 72.9% yield) as a slightly white/hazy clearglass. Rf=0.30 (2:1 hexanes:EtOAc); LCMS calcd for C₄₉H₅₄ClN₂O₈S (M+H)⁺:m/z=865.33; found: 865.2.

Step 4: methyl2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]acetate

A 4 mL vial with septum containing methyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]acetate(50.0 mg, 0.06 mmol) under N₂ was charged with DCM (1 mL) followed byTFA (1.0 mL, 0.06 mmol) and stirred at r.t. overnight. The purplereaction mixture was concentrated under reduced pressure, neutralizedwith sat. sodium bicarbonate (10 mL), diluted with water (30 mL) andextracted with EtOAc (40 mL). The organic layer was washed with water(40 mL), brine (20 mL), and dried over Na₂SO₄. The organic layer wasfiltered, concentrated under reduced pressure, and heat (˜50° C.) toyield methyl2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]acetate(44.1 mg) as a yellow gum. LCMS calculated for C₃₃H₃₈ClN₂O₆S (M+H)⁺:m/z=625.21; found: 625.4.

Step 5:2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]aceticacid

A 20 mL vial containing methyl2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]acetate(40 mg, 0.06 mmol) and lithium hydroxide (8.2 mg, 0.33 mmol) was chargedwith THF (900 μL) and water (300 μL). The vial was purged with N₂ andstirred at r.t. for 2 h. The reaction mixture was diluted with EtOAc (30mL), washed twice with 0.1 M HCl (5 mL) and brine (20 mL), and washedwith brine (20 mL). The organic layer was dried over Na₂SO₄, filtered,concentrated under reduced pressure and heat (−60° C.) to yield crude2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]aceticacid (37 mg, 0.061 mmol, 95% yield) as an off-white glass. LCMScalculated for C₃₂H₃₆ClN₂O₅S (M+H)⁺: m/z=611.20; found: 611.3.

Step 6:(3R,6R,24S)-6′-chloro-17,17-dioxo-spiro[8,22-dioxa-17λ{circumflex over( )}6-thia-1,16-diazapentacyclo[16.7.2.1{circumflex over( )}9,13.0{circumflex over ( )}3,6.0{circumflex over( )}21,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one

A 20 mL vial with septum containing2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]aceticacid (26 mg, 0.04 mmol) in DCM (3 mL) was charged with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg, 0.13mmol) and 4-(dimethylamino)pyridine (25 mg, 0.20 mmol) in one portion.The reaction mixture was stirred at r.t. for 2 h. The reaction mixturewas quenched with 2 drops of water. The reaction mixture was thendiluted with EtOAc (30 mL), washed twice with 0.1 M HCl (3 mL) and water(20 mL), and brine (20 mL). The organic layer was dried over Na₂SO₄,filtered, concentrated under reduced pressure, and purified by FCC (12 gSiO₂, 0→40% EtOAc in hexanes, wet-loaded in DCM+hexanes). Fractionscontaining mostly product were combined and re-purified by FCC (15.5 gC18, 40→95% MeCN in H₂O, wet-loaded in DMSO). Fraction of high puritywere combined, and concentrated under reduced pressure and heat (−60°C.) to yield 96.3% pure(3R,6R,24S)-6′-chloro-17,17-dioxo-spiro[8,22-dioxa-17λ{circumflex over( )}6-thia-1,16-diazapentacyclo[16.7.2.1{circumflex over( )}9,13.0{circumflex over ( )}3,6.0{circumflex over( )}21,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one(8.1 mg, 0.013 mmol, 30% yield) as an off-white solid. R_(f)=0.54 (1:2hexanes:EtOAc). LCMS calculated for C₃₂H₃₄ClN₂O₅S (M+H)⁺: m/z=593.19;found: 593.1; ¹H NMR (500 MHz, Acetonitrile-d₃) δ 9.40 (s, 1H), 7.66 (d,J=8.5 Hz, 1H), 7.20 (dd, J=2.4, 8.5 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H),7.13 (dd, J=2.2, 8.3 Hz, 1H), 7.09 (t, J=7.9 Hz, 1H), 6.92 (d, J=2.2 Hz,1H), 6.83 (t, J=2.1 Hz, 1H), 6.78-6.71 (m, 2H), 6.67 (d, J=7.4 Hz, 1H),4.13-4.02 (m, 4H), 3.46 (d, J=14.5 Hz, 1H), 3.41 (s, 2H), 3.32 (dd,J=5.4, 14.7 Hz, 2H), 3.19 (dd, J=9.5, 14.7 Hz, 1H), 2.84-2.70 (m, 2H),2.64 (h, J=7.5, 8.5 Hz, 1H), 2.60-2.51 (m, 1H), 2.03-1.95 (m, 3H),1.88-1.78 (m, 3H), 1.65-1.55 (m, 2H).

Example 192-Pyridin-4-yl-N-[(3S)-6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-acetamide

This compound was prepared using procedures analogous to those describedfor Example 12 using 2-(pyridin-4-yl)acetic acid to replace acetic acidin Step 3. LCMS calculated for C₃₀H₃₃ClN₃O₄S (M+H)⁺: m/z=566.18; found:566.1. ¹H NMR (500 MHz, DMSO-d₆) δ 12.20 (s, 1H), 8.55 (d, J=5.2 Hz,1H), 7.62 (d, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.27-7.13 (m, 2H), 7.00 (d,J=8.3 Hz, 1H), 4.06 (s, 1H), 3.71 (s, 1H), 2.82-2.65 (m, 1H), 2.02-1.86(m, 2H), 1.84-1.68 (m, 4H), 1.50 (d, J=6.8 Hz, 1H).

Example 203-Pyridin-4-yl-N-[rac-(3S)-6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide

This compound was prepared using procedures analogous to those describedfor Example 12 using 2-(pyridin-4-yl)acetic acid to replace acetic acidin Step 3. LCMS calculated for C₃₁H₃₅ClN₃O₄S (M+H)⁺: m/z=580.2; found:580.2. ¹H NMR (500 MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.51 (s, 1H), 8.00 (s,1H), 7.63 (d, J=8.5 Hz, 2H), 7.29-7.15 (m, 5H), 7.01 (d, J=8.2 Hz, 1H),4.11-4.03 (m, 2H), 3.77 (s, 2H), 3.51 (d, J=14.3 Hz, 1H), 3.35-3.20 (m,3H), 2.82-2.67 (m, 2H), 2.58 (s, 4H), 2.04-1.66 (m, 10H), 1.50 (dd,J=5.5, 12.2 Hz, 1H).

Example 21 tert-Butyl4-[[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 2 using N-Boc-isonipecotic acid to replace acetic acid inStep 2. LCMS calculated for C₃₄H₄₅ClN₃O₆S (M+H)⁺: m/z=658.26; found:657.9.

Example 22 tert-Butyl4-[2-[[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-2-oxo-ethyl]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 2 using 2-(1-tert-butoxycarbonyl-4-piperidyl)acetic acid toreplace acetic acid in Step 2. LCMS calculated for C₃₅H₄₇ClN₃O₆S (M+H)⁺:m/z=672.28; found: 671.9.

Example 23 tert-Butyl(3S)-3-[[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyloxy]piperidine-1-carboxylate

Step 1: tert-butyl (3S)-3-chlorocarbonyloxypiperidine-1-carboxylate

A solution of tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (2.01 g,9.99 mmol) in DCM (20 mL) was cooled to 0° C. and a freshly preparedsolution of triphosgene (1.48 g, 4.99 mmol) in 5 mL of DCM was addeddropwise over 5 minutes. The mixture was stirred at this temperature for30 min., then pyridine (0.81 mL, 9.9 mmol) was added dropwise. Themixture was kept stirring at 0° C. for 1 h. Water (30 mL) was added tothe mixture and the layers were separated. The organic layer was driedover sodium sulfate and concentrated under reduced pressure to affordthe crude product tert-butyl(3S)-3-chlorocarbonyloxypiperidine-1-carboxylate (1.8 g, 68% yield)which was used in next step without further purification.

Step 2: tert-Butyl(3S)-3-[[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyloxy]piperidine-1-carboxylate

A solution of6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Example 1, Step 1, 15 mg, 0.03 mmol) and potassium carbonate (13.8 mg,0.10 mmol) in acetone (2 mL) was stirred for 5 min in a sealed tube.Then a solution of tert-butyl(3S)-3-chlorocarbonyloxypiperidine-1-carboxylate (13.3 mg, 0.05 mmol) inacetone was added. The resulting mixture was stirred at 60° C.overnight, and poured into water (5 mL) and extracted with DCM (5 mL×3).The combined organic layer were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified byprep-HPLC on C18 column to afford desired product tert-butyl(3S)-3-[[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyloxy]piperidine-1-carboxylate(12.1 mg, 53% yield) as a white solid. LCMS calculated for C₃₄H₄₅ClN₃O₇S(M+H)⁺: m/z=674.26; found: 673.9.

Example 24N-[6′-Chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylpyrrolidine-1-carboxamide

To a solution of pyrrolidine (23.8 mg, 0.34 mmol) in THF (2 mL) wasadded triphosgene (49.7 mg, 0.17 mmol). The mixture was kept stirring atr.t. for 2 hrs. Then pyridine was added to the solution. The mixture wasfurther kept stirring at r.t. for 1 h. Then the whole solution wastransferred to a solution of6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Example 1, Step 1, 15.0 mg, 0.03 mmol) and potassium carbonate (4.64mg, 0.03 mmol) in acetone. The mixture was kept stirring at refluxovernight. The mixture was poured into water (5 mL) and the pH ofaqueous was adjusted to 7-8 by adding saturated potassium bicarbonatesolution. The aqueous layer was extracted with DCM (5 mL×3). Thecombined organic layer was dried over sodium sulfate and concentrated.The crude product was further purified prep HPLC on C18 column to affordN-[6′-chloro-5-(cyclobutylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylpyrrolidine-1-carboxamide(9 mg, 47% yield) as a yellow solid. LCMS calculated for C₂₈H₃₅ClN₃O₄S(M+H)⁺: m/z=544.20; found: 543.8.

Example 25(1S,1′R,2′R)-6-Chloro-3,4-dihydro-2H-spiro[naphthalene-1,3′-5,10-dithia-9-aza-1(5,7)-benzo[b][1,4]oxazepina-6(1,3)-benzena-3(1,2)-cyclobutanacyclodecaphan]-8′-one10′,10′-dioxide

Step 1:[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methyl4-methylbenzenesulfonate

To a mixture of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Example 18, Step 2, 44.0 mg, 0.06 mmol), tosyl chloride (16.2 mg, 0.08mmol) in DCM (0.5 mL) was added TEA (22 uL, 0.16 mmol) at r.t. Thereaction mixture was stirred at r.t. for 22 h. The additional tosylchloride (21.2 mg, 0.11 mmol) and TEA (70 μL, 0.50 mmol) were added, andthe reaction mixture was stirred for an additional 3 d at r.t. Thereaction mixture was diluted with EtOAc (30 mL), washed with sat. NH₄Cl(15 mL) and water (15 mL), 0.05N HCl (30 mL), sat. NaHCO₃ (2×20 mL), andbrine (20 mL). The organic layer was dried over Na₂SO₄, filtered,concentrated under reduced pressure to yield crude[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methyl4-methylbenzenesulfonate (65.8 mg) which was directly used in next stepreaction without further purification.

Step 2: methyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylsulfanyl]phenyl]acetate

A mixture of[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methyl4-methylbenzenesulfonate (65.8 mg), methyl 2-(3-sulfanylphenyl)acetate(26.3 mg, 0.12 mmol), and potassium carbonate (21.5 mg, 0.15 mmol) waspurged with N₂, and charged with DMF (400 μL). The mixture was stirredat r.t. overnight. LCMS analysis to form two major products. Thereaction mixture was diluted with EtOAc (30 mL), washed with 0.1 N HCl(3 mL) and water (30 mL), sat. NaHCO₃ (30 mL), and brine (20 mL). Theorganic layer was dried over Na₂SO₄, filtered, concentrated underreduced pressure to yield crude methyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylsulfanyl]phenyl]acetate(74 mg) as a brown solid. Rf=0.34 (2:1 hexanes:EtOAc)

Step 3: methyl2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylsulfanyl]phenyl]acetate

A solution of methyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylsulfanyl]phenyl]acetate(74 mg) in DCM (1.3 mL) and TFA (1.3 mL) was stirred at r.t. for 18 h.The volatiles were removed under reduced pressure. The residue wasco-evaporated with DCM twice under reduced pressure, and purified by FCC(12 g SiO₂, 10→35% EtOAc in hexanes, wet-loaded in DCM) to yield methyl2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylsulfanyl]phenyl]acetate (19.3 mg with ˜80% pure) as a white solid. Rf=0.18 (2:1hexanes:EtOAc); LCMS m/z calcd for C₃₃H₃₈ClN₂O₅S₂ (M+H)⁺:m/z=641.19/643.19; found: 641.2/643.1.

Step 4:2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylsulfanyl]phenyl]aceticacid

Methyl2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylsulfanyl]phenyl]acetate(19.0 mg, 0.02 mmol) in THF (400 uL) was treated with lithium hydroxide(6.0 mg, 0.24 mmol) in water (130 μL) at r.t. The reaction mixture wasstirred at r.t. for 4 h. The mixture was diluted with EtOAc (20 mL),washed with water (5 mL), 0.1 N HCl (4 mL), and brine (15 mL). Theaqueous layer was separated and extracted again with EtOAc (20 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to yield2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylsulfanyl]phenyl]aceticacid (29 mg) as an opaque yellow gum. LCMS m/z called for C₃₂H₃₆ClN₂O₅S₂(M+H)⁺: m/z=627.17/629.17; found: 627.1/629.1.

Step 5:(1S,1′R,2′R)-6-chloro-3,4-dihydro-2H-spiro[naphthalene-1,3′-5,10-dithia-9-aza-1(5,7)-benzo[b][1,4]oxazepina-6(1,3)-benzena-3(1,2)-cyclobutanacyclodecaphan]-8′-one10′,10′-dioxide

A solution of2-[3-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylsulfanyl]phenyl]acetic acid (29 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (26.0 mg,0.14 mmol) in DCM (1.5 mL) was charged with 4-(dimethylamino)pyridine(27.0 mg, 0.22 mmol). The mixture was purged with N₂ and stirred at r.t.for 20 h. The reaction mixture was diluted with EtOAc (30 mL), washedtwice with 1 N HCl (3 mL) and brine (20 mL). The aqueous layers werecombined and back-extracted with DCM (3×20 mL). The organic combinedlayers were dried over Na₂SO₄, and filtered, and concentrated underreduced pressure. The residue was purified by FCC (15.5 g C18, 20→100%MeCN in H₂O, wet-loaded in DMSO). Fractions containing clean desiredproduct were combined and concentrated under reduced pressure to yield(1S,1′R,2′R)-6-chloro-3,4-dihydro-2H-spiro[naphthalene-1,3′-5,10-dithia-9-aza-1(5,7)-benzo[b][1,4]oxazepina-6(1,3)-benzena-3(1,2)-cyclobutanacyclodecaphan]-8′-one10′,10′-dioxide (5.5 mg) as a white solid. LCMS m/z calcd forC₃₂H₃₄ClN₂O₄S₂ (M+H)⁺: m/z=609.16/611.16; found: 609.0/611.0. ¹H NMR(500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.45(dd, J=2.1, 8.4 Hz, 1H), 7.28 (d, J=4.2 Hz, 2H), 7.21 (dd, J=2.3, 8.5Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.07 (s, 1H), 7.03 (t, J=4.7 Hz, 1H),6.97 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H), 4.23 (d, J=12.1 Hz, 1H),4.08 (d, J=12.0 Hz, 1H), 3.61 (AB_(q), 2H, J_(AB)=14.8 Hz, Δδ_(AB)=0.017Hz), 3.46 (d, J=14.4 Hz, 1H), 3.38-3.27 (m, 2H), 3.07 (dt, J=6.8, 13.6Hz, 2H), 2.84-2.73 (m, 3H), 2.26 (ddd, J=7.7, 15.0, 31.3 Hz, 2H), 2.06(dtd, J=2.6, 8.0, 10.9 Hz, 1H), 1.98-1.75 (m, 3H), 1.66 (p, J=9.0 Hz,2H), 1.61-1.48 (m, 2H).

Example 26(3R,6R,7R,8E,23S)-6′-Chloro-7-methoxy-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one

Step 1: 1-[(tert-butoxycarbonylamino)methyl]cyclobutanecarboxylic acid

To a suspension of 1-(aminomethyl)cyclobutanecarboxylic acidhydrochloride salt (500 mg, 3.02 mmol) and sodium bicarbonate (1014 mg,12.0 mmol) in THF (5 mL) and water (5 mL) was added di-tert-butyldicarbonate (790 mg, 3.62 mmol). The resulting mixture was heated at 40°C. for 3 h. The reaction was acidified with 0.5 N HCl (to pH 4-5) andextracted with MTBE. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withEtOAc/Hept (15% to 40%) to afford1-[(tert-butoxycarbonylamino)methyl]cyclobutanecarboxylic acid (520 mg,75% yield). LCMS: calc. for C₁₁H₁₈NO₄ (M−H)⁻: m/z=228.12; Found: 228.17.

Step 2: 1-[[allyl(tert-butoxycarbonyl)amino]methyl]cyclobutanecarboxylicacid

To a solution of1-[(tert-butoxycarbonylamino)methyl]cyclobutanecarboxylic acid (520 mg,2.27 mmol) in THF (10 mL) was slowly added sodium hydride (272 mg, 6.8mmol) at r.t. After 20 min, allyl bromide (411 mg, 3.4 mmol) was addedin one portion. The resulting slurry was heated to a gentle reflux for48 h. The reaction was cool to r.t., concentrated under reducedpressure, charged with EtOAc, and acidified with 0.5 N HCl (to pH 4-5).The layers were separated, and the aqueous phase was extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated under reduced pressure The residue was purifiedby flash chromatography on a silica gel column with EtOAc/Hept (10% to30%) to afford1-[[allyl(tert-butoxycarbonyl)amino]methyl]cyclobutanecarboxylic acid(203 mg, 33% yield) as a yellow oil. LCMS: calc. for C₁₄H₂₂NO4 (M−H)⁻:m/z=268.16, Found: 268.13.

Step 3: tert-butylN-allyl-N-[[1-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]cyclobutyl]methyl]carbamate

A mixture of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(120.0 mg, 0.23 mmol, Intermediate 8),1-[[allyl(tert-butoxycarbonyl)amino]methyl]cyclobutanecarboxylic acid(125 mg, 0.46 mmol), DMAP (170 mg, 1.39 mmol) and EDCI (0.27 mL, 1.39mmol) was stirred at r.t. for 4 h. The reaction was diluted with CH2C12and washed with 0.5 N HCl. The organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column (12 g) usingEtOAc/Heptanes (5% to 50%) to afford tert-butylN-allyl-N-[[1-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]cyclobutyl]methyl]carbamate(180 mg) as a colorless oil. LCMS: calc. for C₄₁H₅₅ClN₃O₇S [M+H]⁺:m/z=768.34/770.34; Found: 768.14/770.47.

Step 4:(3R,6R,7R,8E,23S)-6′-chloro-7-methoxy-11-(tert-butoxycarbonyl)-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one

A solution of tert-butylN-allyl-N-[[1-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]cyclobutyl]methyl]carbamate(180 mg, 0.23 mmol) in DCE (90 mL) was bubbled with N₂ for 10 min.(1,3-Dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI)chloride; Hoveyda-Grubbs II (29.3 mg, 0.05 mmol) was added and theresulting greenish solution was further bubbled with N₂ for 5 min, andwas heated to reflux under N₂ for 16 h. LC-MS analysis indicated thecompletion of reaction. The reaction was allowed to cool to r.t. whilebeing exposed to air. The reaction was concentrated under reducedpressure, and the residue was purified by flash chromatography on asilica gel column (12 g) using EtOAc/Heptanes (5% to 60%) to afford(3R,6R,7R,8E,23S)-6′-chloro-7-methoxy-11-(tert-butoxycarbonyl)-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one(140 mg, 80% yield). LC-MS: [M+H]⁺ calc. for C₃₉H₅₁ClN₃O₇S:740.31/742.31; Found: 739.96/742.29.

Step 5:(3R,6R,7R,8E,23S)-6′-chloro-7-methoxy-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one

(3R,6R,7R,8E,23S)-6′-Chloro-7-methoxy-11-(tert-butoxycarbonyl)-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one(140.0 mg, 0.19 mmol) in 2 N HCl in EtOAc (3 mL) was stirred at r.t.overnight. The reaction was diluted with EtOAc, washed with saturatedaqueous NaHCO₃solution and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the crude product (120mg). 40 mg of the crude product was purified by prep-HPLC on C18 column(30×250 mm, 10 m) with 20 to 100% ACN/H₂O to afford the desired(3R,6R,7R,8E,23S)-6′-chloro-7-methoxy-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one(19 mg) as a white solid. LCMS: calc. for C₃₄H₄₃ClN₃O₅S [M+H]⁺:m/z=640.26/642.26; Found: 639.96/642.23. ¹H NMR (600 MHz, CDCl₃) δ 7.69(d, J=8.5 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.27 (d, 1H, overlapped withCDCl₃), 7.17 (dd, J=8.5, 2.3 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.96 (d,J=8.3 Hz, 1H), 5.90 (app s, 1H), 5.62 (dd, J=15.6, 8.0 Hz, 1H), 4.07 (t,J=9.3 Hz, 2H), 3.74 (d, J=14.4 Hz, 1H), 3.54 (app s, 1H), 3.41 (app s,1H), 3.28 (d, J=14.6 Hz, 1H), 3.25 (s, 3H), 3.18-3.10 (m, 1H), 3.02 (d,J=13.4 Hz, 1H), 2.89-2.71 (m, 2H), 2.63-2.42 (m, 2H), 2.26 (app s, 1H),2.09-1.77 (m, 8H), 1.62-1.50 (m, 9H).

Example 27(3R,6R,7R,8E,23S)-6′-Chloro-7-methoxy-11-methyl-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one

To a solution of(3R,6R,7R,8E,23S)-6′-chloro-7-methoxy-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one(40.0 mg, 0.06 mmol, Example 26) in DCM (5 mL) was added acetic acid(0.02 mL, 0.31 mmol) and formaldehyde solution (37% wt %, 51 mg, 0.625mmol HCHO). After 2 h, the reaction mixture was cooled at 0° C. andsodium borohydride (47.2 mg, 1.25 mmol) was added in portions. Thereaction was stirred at r.t. for 3 h, and diluted with DCM and water,filtered through a pad of Celite. The organic layer was washed withsaturated aqueous NaHCO₃solution and brine, dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified byprep-HPLC on C18 column (30×250 mm, 10 m) with 20 to 100% ACN/H₂O toafford(3R,6R,7R,8E,23S)-6′-chloro-7-methoxy-11-methyl-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one(20 mg, 48.9% yield). LCMS: calc. for C₃₅H₄₅ClN₃O₅S [M+H]⁺:m/z=654.28/656.27; Found: 654.02/656.36. ¹H NMR (600 MHz, CDCl₃) δ 13.75(br s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.54 (dd, J=8.3, 2.1 Hz, 1H), 7.17(dd, J=8.5, 2.3 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H),6.95 (br s, 1H), 6.12-6.03 (m, 1H), 5.53 (dd, J=15.8, 8.8 Hz, 1H), 4.06(s, 2H), 3.72 (d, J=14.6 Hz, 1H), 3.60 (t, J=8.5 Hz, 1H), 3.52 (q,J=12.8, 11.3 Hz, 1H), 3.31 (d, J=14.7 Hz, 1H), 3.28 (s, 3H), 3.19 (q,J=13.4, 9.2 Hz, 1H), 3.09 (t, J=11.4 Hz, 1H), 2.96 (dd, J=15.1, 11.2 Hz,1H), 2.87 (d, J=13.8 Hz, 1H), 2.83-2.66 (m, 3H), 2.60-2.52 (m, 1H), 2.45(app s, 5H), 2.15-1.58 (m, 13H).

Example 28(3R,6R,7S,8E,22S)-6′-Chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[[11,20]dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

Step 1: methyl 1-(allyloxy)cyclopropane-1-carboxylate

NaH (1.03 g, 25.84 mmol) washed by ether (30 mL) was added in oneportion to a solution of methyl 1-hydroxycyclopropanecarboxylate (2.0 g,17.22 mmol) in THF (20 mL). The reaction mixture was stirred at r.t. for1 h. Allyl bromide (2.08 g, 17.2 mmol) was added, and the reactionmixture was stirred at r.t. for 14 h., then quenched with saturatedaqueous NH₄Cl (20 mL). The resulting mixture was extracted with ether(3×30 mL). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, and filtered. The filtrate was concentrated bydecompression distillation at 0° C. to give methyl1-(allyloxy)cyclopropane-1-carboxylate (1.2 g, 44% yield) as colorlessoil. ¹H NMR (400 MHz, DMSO-d₆) δ 5.91-5.83 (m, 1H), 5.24-5.19 (m, 1H),5.12-5.09 (m, 1H), 4.096-4.06 (m, 2H), 3.65 (s, 3H), 1.19-1.17 (m, 4H).

Step 2: 1-(allyloxy)cyclopropane-1-carboxylic acid

NaOH (1.5 g, 37.5 mmol) was added to a solution of methyl1-allyloxycyclopropanecarboxylate (1.2 g, 7.68 mmol) in methanol (5 mL)and water (5 mL). The reaction mixture was stirred at r.t. for 14 h. Tothe reaction mixture was added 20 mL of water. The resulting mixture wasextracted with DCM (3×20 mL), then adjusted with HCl (3 M) to pH 2˜3,extracted with DCM (5 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated to give thecrude product 1-allyloxycyclopropanecarboxylic acid (369 mg, 34% yield)which was used directly in next step reaction without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (br s, 1H), 5.92-5.82(m, 1H), 5.20 (ddd, J=17.3, 3.8, 1.8 Hz, 1H), 5.09 (ddd, J=10.5, 3.4,1.5 Hz, 1H), 4.07 (dt, J=5.4, 1.6 Hz, 2H), 1.15-1.14 (m, 2H), 1.11-1.09(m, 1H).

Step 3:(3R,6R,7S,8E,22S)-6′-chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[[11,20]dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and 1-(allyloxy)cyclopropane-1-carboxylic acid in Step3. LC-MS calc. for C₃₂H₃₈ClN₂O₆S [M+H]⁺: m/z=613.2/615.2. Found:612.8/615.1. ¹H NMR (600 MHz, DMSO-d₆) δ 11.73 (s, 1H), 7.58 (d, J=8.4Hz, 1H), 7.33 (d, J=15.7 Hz, 1H), 7.27-7.19 (m, 3H), 7.08 (d, J=14.5 Hz,1H), 5.66-5.57 (m, 1H), 5.09-5.01 (m, 1H), 4.14 (d, J=11.9 Hz, 1H),4.09-4.03 (m, 1H), 4.00 (d, J=12.0 Hz, 1H), 3.93 (dd, J=12.7, 9.3 Hz,1H), 3.52 (d, J=14.2 Hz, 1H), 3.33-3.28 (m, 2H), 3.16-3.05 (m, 2H), 3.02(s, 3H), 2.84-2.71 (m, 2H), 2.11-2.05 (m, 1H), 2.06-1.97 (m, 1H),1.88-1.80 (m, 3H), 1.78-1.72 (m, 3H), 1.56 (q, J=9.3 Hz, 1H), 1.40-1.37(m, 1H), 1.27-1.23 (m, 2H), 1.07-1.05 (m, 2H).

Example 29(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[[11,20]dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and 1-(allyloxy)cyclopropane-1-carboxylic acid in Step3. LC-MS calc. for C₃₂H₃₈ClN₂O₆S [M+H]⁺: m/z=613.2/615.2. Found:613.2/615.1. ¹H NMR (600 MHz, DMSO-d₆) 11.79 (S, 1H), 7.67 (d, J=8.5 Hz,1H), 7.30 (dd, J=8.5, 2.3 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.21-7.20 (m,2H), 7.05 (d, J=8.2 Hz, 1H), 5.67-5.63 (m, 1H), 5.40 (dd, J=15.4, 8.5Hz, 1H), 4.16-4.05 (m, 3H), 3.80 (dd, J=13.1, 7.2 Hz, 1H), 3.63-3.57 (m,2H), 3.09-3.05 (m, 4H), 2.83-2.80 (m, 1H), 2.75-2.69 (m, 1H), 2.64-2.59(m, 1H), 2.29-2.27 (m, 1H), 2.00 (d, J=13.7 Hz, 1H), 1.88-1.82 (m, 3H),1.76-1.61 (m, 3H), 1.44-1.41 (m, 1H), 1.26-1.14 (m, 3H), 1.06-1.04 (m,1H).

Example 30(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-12,12-dimethyl-15,15-dioxo-spiro[[11,20]dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

Step 1: 2-allyloxy-2-methyl-propanoic acid

This compound was prepared using procedures analogous to those describedfor Example 28 Step 1-2 using ethyl 2-hydroxy-2-methyl-propanoate toreplace methyl 1-hydroxycyclopropanecarboxylate in Step 1.

Step 2:(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-dimethyl15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and 1-(allyloxy)cyclopropane-1-carboxylic acid in Step3. LC-MS calc. for C₃₂H₄₀ClN₂O₆S [M+H]⁺: m/z=615.22/617.22. Found:614.8/617.1. ¹H-NMR (600 MHz, CDCl₃) δ 9.07 (s, 1H), 7.67 (d, J=8.5 Hz,1H), 7.51 (d, J=8.2 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.08 (d, J=2.0 Hz,1H), 6.99 (dd, J=8.7, 5.1 Hz, 2H), 5.83 (d, J=15.4 Hz, 1H), 5.53 (dd,J=15.6, 8.5 Hz, 1H), 4.11 (dt, J=21.2, 7.1 Hz, 3H), 3.77 (d, J=12.2 Hz,1H), 3.72 (d, J=14.7 Hz, 1H), 3.59-3.44 (m, 2H), 3.33 (d, J=14.7 Hz,1H), 3.27 (s, 3H), 3.07 (dd, J=15.0, 9.9 Hz, 1H), 2.84-2.67 (m, 2H),2.58-2.44 (m, 1H), 2.25-2.13 (m, 1H), 2.04-1.89 (m, 4H), 1.87-1.77 (m,1H), 1.65-1.52 (m, 3H), 1.42 (s, 3H), 1.38 (s, 3H).

Example 31(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

Step 1: ethyl 1-hydroxycyclobutanecarboxylate

To a solution of ethyl 1-aminocyclobutanecarboxylate hydrochloride(501.2 mg, 2.79 mmol) in aqueous sulfuric acid (11.2 mL, 5.6 mmol) at 0°C. was dropwise added a solution of sodium nitrite (980 mg, 14 mmol) inwater (3 mL). The reaction was stirred at 0° C. for 1 h and allowed towarm to r.t. After 24 h., the reaction was extracted with MTBE. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to give ethyl1-hydroxycyclobutane-1-carboxylate as colorless oil (240 mg). The crudeproduct was used in next step without further purification. TLC: Rf=0.38(3:7 EtOAc/Hept).

Step 2: I-allyloxycyclobutanecarboxylic acid

This compound was prepared using procedures analogous to those describedfor Example 28 Step 1-2 using ethyl 1-hydroxycyclobutane-1-carboxylateto replace methyl 1-hydroxycyclopropanecarboxylate in Step 1. LC-MScalc. for C₈H₁₁O₃ [M−H]⁻: m/z=155.1; Found: 155.1.

Step 3:(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and 1-allyloxycyclobutanecarboxylic acid in Step 3.LC-MS calc. for C₃₃H₄₀ClN₂O₆S [M+H]⁺: m/z=627.23/629.23. Found:626.9/629.0. ¹H-NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 7.73 (d, J=8.5 Hz,1H), 7.53 (d, J=8.5 Hz, 1H), 7.23 (s, 1H), 7.20 (d, J=10.1 Hz, 1H), 7.10(s, 1H), 6.97 (d, J=8.3 Hz, 1H), 5.90-5.79 (m, 2H), 4.29-3.63 (m, 8H),3.33 (s, 3H), 3.27 (d, J=14.5 Hz, 1H), 3.00 (dd, J=15.2, 10.5 Hz, 1H),2.84-2.72 (m, 2H), 2.70-2.59 (m, 1H), 2.37 (s, 2H), 2.10-1.16 (m, 12H).

Example 32(3R,6R,7S,8E,22S)-6′-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-oneand Example 33(3R,6R,7S,8Z,22S)-6′-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1:[(1S)-1-[(R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propanoyl)sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]2-allyloxy-2-methyl-propanoate

A solution of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(200.0 mg, 0.40 mmol, Intermediate 3), 2-allyloxy-2-methyl-propanoicacid (171.96 mg, 1.19 mmol, Example 30, Step 1), EDCI (0.47 mL, 2.39mmol), and DMAP (291.43 mg, 2.39 mmol) in DCM (4 mL) was stirred at r.t.for 16 h. LC-MS indicated the completion of reaction. The reaction wasdiluted with DCM and washed with 0.5 N HCl. The organic phase was driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column (12 g) withEtOAc/Heptanes (10% to 20%) to afford[(1S)-1-[(1R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propanoyl)sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]2-allyloxy-2-methyl-propanoate (300 mg, 99.9% yield). LC-MS: calc. forC₄₀H₅₂ClN₂O₈S [M+H]⁺: m/z=755.31/757.31; Found: 755.1/757.4.

Step 2:2-allyloxy-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide

A solution of[(1S)-1-[(1R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propanoyl)sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]2-allyloxy-2-methyl-propanoate (300 mg, 0.40 mmol) and lithium hydroxidemonohydrate (83.3 mg, 1.99 mmol) in THF/MeOH/H₂O (0.3 mL each) washeated at 45° C. for 4 h. LC-MS indicated the completion of reaction.The reaction was adjusted with 1 N HCl to pH 3-4 and extracted with DCM.The combined organic layers were washed with saturated aqueousNaHCO₃solution and brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to afford2-allyloxy-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide(175 mg, 70% yield), which was used without further purifications. LCMS:calc. for C₃₃H₄₂ClN₂O₆S [M+H]⁺: m/z=629.24/631.24; Found: 628.9/631.2.

Step 3:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

A solution of2-allyloxy-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-propanamide(1.40 g, 2.23 mmol) in DCE (1230 mL) was bubbled with N₂ for 10 min.1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (Zhan Catalyst1B) (326 mg, 0.45 mmol) was added and the resulting greenish solutionwas further bubbled with N₂ for 5 min., and was heated at 40° C. underN₂ for 2 h. The reaction was concentrated under reduced pressure, andthe residue purified by flash column chromatography on a silica gelcolumn with EtOAc/Hept (10% to 70%) to afford two products: P1 (theearlier eluted product, 160 mg, 11% yield) and P2 (the latter elutedproduct, 647 mg, 47% yield).

P2 was assigned to(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 32). HPLC: major product, C18 column (4.6×150 mm, 100 Å); flowrate=1 mL/min; mobile phase: 90% MeCN/H₂O (with 0.1% HCO₂H) 10 min λ=220nm. tR=3.2 min. LC-MS calc. for C₃₁H₃₈ClN₂O₆S [M+H]⁺: m/z=601.21/603.21;Found 601.6/603.6; ¹H NMR (300 MHz, CDCl₃) δ 9.15 (s, 1H), 7.69 (d,J=8.5 Hz, 1H), 7.53 (dd, J=8.3, 2.1 Hz, 1H), 7.20 (dd, J=8.6, 2.2 Hz,1H), 7.12 (s, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H),5.84-5.72 (m, 2H), 4.24 (d, J=3.3 Hz, 1H), 4.13 (t, J=7.2 Hz, 2H), 4.00(dd, J=13.2, 4.5 Hz, 1H), 3.88 (d, J=12.5 Hz, 1H), 3.72 (d, J=14.6 Hz,1H), 3.40-3.24 (m, 3H), 2.84-2.71 (m, 3H), 2.43-2.33 (m, 1H), 2.01 (d,J=15.5 Hz, 2H), 1.94-1.81 (m, 4H), 1.75-1.58 (m, 2H), 1.54 (d, J=14.5Hz, 1H), 1.45 (s, 3H), 1.41 (s, 3H).

And P1 to(3R,6R,7S,8Z,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 33). P1: minor product, C18 column (4.6×150 mm, 100 Å); flowrate=1 mL/min; mobile phase: 90% MeCN/H₂O (with 0.1% HCO₂H) 10 min λ=220nm. tR=4.3 min. LC-MS calc. for C₃₁H₃₈ClN₂O₆S [M+H]⁺: m/z=601.21/603.21;Found 601.6/603.6; ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 1H), 7.68 (t,J=8.3 Hz, 1H), 7.55 (dd, J=8.4, 2.1 Hz, 1H), 7.20 (dd, J=8.5, 2.1 Hz,1H), 7.13 (dd, J=9.6, 2.0 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 5.92-5.75 (m,2H), 4.22-4.14 (m, 1H), 4.00 (dd, J=13.4, 4.9 Hz, 1H), 3.89 (dd, J=13.3,2.9 Hz, 1H), 3.81-3.61 (m, 4H), 3.33 (d, J=14.5 Hz, 1H), 3.15 (dd,J=15.1, 9.2 Hz, 1H), 2.79 (d, J=9.2 Hz, 2H), 2.53 (d, J=5.2 Hz, 1H),2.33-2.22 (m, 1H), 2.08-1.92 (m, 4H), 1.81 (dd, J=35.4, 6.4 Hz, 2H),1.71-1.57 (m, 2H), 1.45 (s, 3H), 1.42 (s, 3H).

Example 34[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

To a solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(13.0 mg, 0.02 mmol, Example 32) in THF (0.5 mL) was added sodiumhydride (4.3 mg, 0.11 mmol) at r.t. After 10 min, N,N-dimethylcarbamoylchloride (4.6 mg, 0.04 mmol) was added, and followed by DMAP (5.3 mg,0.04 mmol). The mixture was stirred at r.t. for 6 h., and diluted withDCM and acidified with 0.5 N HCl to pH 5-6. The organic phase wasseparated, washed with water and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC on C18 column (30×250 mm, 10 m) with 20 to 100% ACN/H₂O toafford[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate (6 mg, 38% yield) as a white solid. LCMS: calc.for C₃₄H₄₃ClN₃O₇S [M+H]⁺: m/z=672.25/674.25; Found: 672.45/674.37. ¹HNMR (600 MHz, CDCl₃) δ 9.08 (br s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.49(dd, J=8.3, 2.2 Hz, 1H), 7.17 (dd, J=8.5, 2.4 Hz, 1H), 7.08 (d, J=2.2Hz, 1H), 7.04-6.95 (m, 2H), 5.86-5.78 (m, 1H), 5.74-5.67 (m, 1H), 5.30(t, J=4.5 Hz, 1H), 4.15 (d, J=12.2 Hz, 1H), 4.12-4.05 (m, 2H), 3.76-3.72(m, 1H), 3.70 (d, J=14.8 Hz, 1H), 3.43 (dd, J=15.1, 4.7 Hz, 1H), 3.37(d, J=14.7 Hz, 1H), 3.21 (dd, J=15.1, 9.3 Hz, 1H), 2.95 (d, J=14.6 Hz,6H), 2.83-2.73 (m, 3H), 2.37 (dtd, J=15.2, 10.2, 9.7, 5.5 Hz, 1H),2.06-1.90 (m, 3H), 1.88-1.77 (m, 3H), 1.67-1.60 (m, 2H), 1.56 (s, 2H),1.43 (s, 6H).

Example 35[(3R,6R,7S,8Z,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34 using(3R,6R,7S,8Z,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 33) and N,N-dimethylcarbamoyl chloride. LC-MS calc. forC₃₄H₄₃ClN₃O₇S [M+H]⁺: m/z=672.24/674.24; Found: 672.6/674.6.

Example 36(3R,6R,7R,8E,22S)-6′-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 32 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) to replace(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) in Step 2. LC-MS calc. for C₃₁H₃₈ClN₂O₆S [M+H]⁺:m/z=601.21/603.21; Found: 600.9/602.8. ¹H NMR (600 MHz, DMSO-d₆) δ 11.87(s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.26 (dd, J=14.2, 5.6 Hz, 2H), 7.18 (d,J=1.9 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.89 (s, 1H), 5.83 (d, J=12.7 Hz,1H), 5.49 (dd, J=15.6, 7.9 Hz, 1H), 4.85 (d, J=4.0 Hz, 1H), 4.09 (dd,J=29.6, 12.2 Hz, 2H), 3.99 (dd, J=13.4, 7.4 Hz, 1H), 3.74 (dd, J=11.8,8.0 Hz, 1H), 3.60 (d, J=14.6 Hz, 1H), 3.45 (d, J=12.5 Hz, 1H), 3.38 (dd,J=21.8, 9.7 Hz, 2H), 3.08 (dd, J=14.8, 10.0 Hz, 1H), 2.81 (d, J=16.9 Hz,1H), 2.75-2.67 (m, 1H), 2.37-2.30 (m, 1H), 2.03-1.77 (m, 6H), 1.63 (ddd,J=30.2, 19.2, 10.3 Hz, 2H), 1.44 (dd, J=19.1, 9.3 Hz, 1H), 1.34 (s, 3H),1.21 (s, 3H) ppm.

Example 37[(3R,6R,7R,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34 using(3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 36) and N,N-dimethylcarbamoyl chloride. LC-MS calc. forC₃₄H₄₃ClN₃O₇S [M+H]⁺: m/z=672.24/674.24; Found: 672.0/674.2. ¹H NMR (600MHz, CDCl₃) δ 9.27 (br s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.3,2.2 Hz, 1H), 7.18 (dd, J=8.5, 2.4 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 7.04(d, J=2.2 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 5.85 (dt, J=15.6, 4.2 Hz,1H), 5.80-5.73 (m, 1H), 5.08 (dd, J=7.9, 5.0 Hz, 1H), 4.11 (d, J=12.1Hz, 1H), 4.06 (d, J=12.1 Hz, 1H), 4.05-3.96 (m, 2H), 3.79 (d, J=14.5 Hz,1H), 3.73 (dd, J=15.2, 3.8 Hz, 1H), 3.27 (d, J=14.5 Hz, 1H), 3.08 (dd,J=15.3, 9.8 Hz, 1H), 2.96 (s, 3H), 2.92 (s, 3H), 2.77 (dddd, J=22.3,16.7, 11.4, 4.6 Hz, 3H), 2.54 (td, J=13.0, 11.6, 6.5 Hz, 1H), 2.41 (qd,J=9.4, 4.9 Hz, 1H), 2.05-1.78 (m, 6H), 1.66 (tq, J=14.6, 7.5, 6.4 Hz,2H), 1.55 (qd, J=10.4, 8.5 Hz, 1H), 1.40 (s, 3H), 1.36 (s, 3H).

Example 38(3R,6R,7R,8E,22S)-6′-Chloro-7-hydroxy-12,12-ethylene-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 32 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 4) and 1-allyloxycyclopropanecarboxylic acid (Example 28,Step 2) in Step 1. LCMS: calc. for C₃₁H₃₆ClN₂O₆S [M+H]⁺:m/z=599.20/601.19; Found: 599.4/601.5. ¹H NMR (600 MHz, DMSO-d₆) δ 11.68(br, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz, 1H),7.27-7.15 (m, 3H), 7.01 (dd, J=12.3, 5.6 Hz, 1H), 5.58-5.47 (m, 2H),4.76 (d, J=4.5 Hz, 1H), 4.10 (d, J=12.0 Hz, 1H), 4.04-3.95 (m, 2H),3.84-3.76 (m, 1H), 3.69-3.57 (m, 2H), 3.03 (d, J=14.5 Hz, 1H), 2.86-2.77(m, 1H), 2.70 (dt, J=16.9, 8.6 Hz, 1H), 2.05-1.95 (m, 2H), 1.87-1.78 (m,3H), 1.74-1.68 (m, 2H), 1.62-1.58 (m, 1H), 1.49-1.45 (m, 1H), 1.41 (td,J=15.3, 8.3 Hz, 1H), 1.32-1.10 (m, 6H).

Example 39[(3R,6R,7R,8E,22S)-6′-Chloro-12,12-ethylene-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34 using(3R,6R,7R,8E,22S)-6′-Chloro-7-hydroxy-12,12-ethylene-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(Example 38) and N,N-dimethylcarbamoyl chloride. LCMS: calc. forC₃₄H₄₁ClN₃O₇S [M+H]⁺: m/z=670.24/672.23; Found: 670.84/672.86. ¹H NMR(600 MHz, CDCl₃) δ 9.04 (s, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.49 (dd,J=8.3, 2.1 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.5, 2.3 Hz,1H), 7.08 (d, J=2.3 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 5.71 (app q, J=2.6Hz, 2H), 4.88 (d, J=3.0 Hz, 1H), 4.13 (d, J=12.1 Hz, 1H), 4.05-3.99 (m,2H), 3.96-3.91 (m, 1H), 3.85 (d, J=14.4 Hz, 1H), 3.82-3.76 (m, 1H), 3.18(d, J=14.5 Hz, 1H), 3.06 (dd, J=15.3, 5.7 Hz, 1H), 2.91 (s, 3H), 2.84(s, 3H), 2.76 (dt, J=11.0, 5.4 Hz, 2H), 2.56 (tt, J=10.7, 5.2 Hz, 2H),2.03-1.85 (m, 4H), 1.83-1.63 (m, 2H), 1.72-1.64 (m, 1H), 1.44 (td,J=13.6, 13.1, 2.6 Hz, 1H), 1.38 (q, J=3.2 Hz, 2H), 1.24-1.19 (m, 1H),1.18-1.11 (m, 1H).

Example 40(3R,6R,7S,8E,22S)-6′-Chloro-7-hydroxy-12,12-ethylene-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 32 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 3) and 1-allyloxycyclopropanecarboxylic acid (Example 28,Step 2) in Step 1. LCMS: calc. for C₃₁H₃₆ClN₂O₆S [M+H]⁺:m/z=599.20/601.19; Found: 599.7/601.6. ¹H NMR (300 MHz, CDCl₃) δ 9.09(s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.31 (s, 1H),7.18 (d, J=8.6 Hz, 1H), 7.10 (d, J=1.9 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H),5.86 (dd, J=15.5, 4.2 Hz, 1H), 5.69-5.51 (m, 1H), 4.19-4.02 (m, 3H),3.96 (dd, J=12.0, 6.7 Hz, 2H), 3.74 (d, J=14.5 Hz, 1H), 3.54 (dd,J=15.0, 8.1 Hz, 1H), 3.33 (dd, J=17.5, 7.5 Hz, 2H), 2.79 (dd, J=9.1, 5.2Hz, 2H), 2.64 (dd, J=14.6, 8.3 Hz, 1H), 2.55-2.41 (m, 1H), 2.10-1.77 (m,3H), 1.65 (ddd, J=35.5, 23.7, 11.9 Hz, 3H), 1.51-1.41 (m, 2H), 1.41-1.31(m, 2H), 1.23 (ddd, J=17.1, 9.8, 5.4 Hz, 3H).

Example 41[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-ethylene-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34 using(3R,6R,7S,8E,22S)-6′-Chloro-7-hydroxy-12,12-ethylene-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(Example 40) and N,N-dimethylcarbamoyl chloride. LCMS: calc. forC₃₄H₄₁ClN₃O₇S [M+H]⁺: m/z=670.24/672.23; Found: 670.84/672.73. ¹H NMR(600 MHz, CDCl₃) δ 9.16 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.45 (dd,J=8.3, 2.2 Hz, 1H), 7.25 (d, J=2.3 Hz, 1H), 7.16 (dd, J=8.5, 2.4 Hz,1H), 7.07 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 5.79-5.65 (m, 2H),5.21-5.17 (m, 1H), 4.15 (d, J=12.2 Hz, 1H), 4.10 (d, J=12.1 Hz, 1H),4.06-3.98 (m, 2H), 3.63 (d, J=14.7 Hz, 1H), 3.54 (dd, J=15.3, 7.6 Hz,1H), 3.31 (d, J=14.7 Hz, 1H), 3.22 (dd, J=15.2, 6.5 Hz, 1H), 2.85 (s,3H), 2.82-2.71 (m, 3H), 2.63 (s, 3H), 2.55 (qd, J=8.8, 6.2 Hz, 1H),2.09-1.87 (m, 4H), 1.78 (tdd, J=20.5, 10.8, 6.3 Hz, 2H), 1.63 (p, J=9.8Hz, 1H), 1.50-1.42 (m, 1H), 1.41-1.33 (m, 2H), 1.30-1.23 (m, 1H),1.20-1.12 (m, 1H).

Example 42(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: 2-[allyl(tert-butoxycarbonyl)amino]-2-methyl-propanoic acid

To a stirred solution of2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (2.0 g, 9.84 mmol)in THF (40 mL) was added sodium hydride (0.98 g, 24.6 mmol) in portionsunder an ice bath. The resulting solution was stirred at r.t. for 10minutes. Then Allyl bromide (2.13 mL, 24.6 mmol) was added. The reactionwas stirred at 50° C. for 24 h. The reaction was quenched with saturatedNH₄Cl solution (40 mL). The mixture was extracted with EtOAc (40 mL×3).The combined organic layers were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column (40 g) with EtOAc/Heptanes (5% to80%) to afford 2-[allyl(tert-butoxycarbonyl)amino]-2-methyl-propanoicacid (1.6 g, 66% yield) as a white solid. LC-MS calc. for C₁₂H₂₀NO₄[M−H]⁻: m/z=242.1; Found: 242.1.

Step 2: tert-butylN-[1,1-dimethyl-2-oxo-2-[[(3S)-6′-chloro-5-[[(R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]ethyl]carbamate

To a stirred solution of2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (176.87 mg, 0.87mmol) in DCM (5 mL) was added DMAP (212 mg, 1.74 mmol) followed by EDCI(135 mg, 0.87 mmol). The resulting mixture was stirred at r.t. for 10min. Then(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(150.0 mg, 0.29 mmol, Intermediate 8) was added. The reaction wasstirred at 40° C. for 8 h. LC-MS showed full conversion of startingmaterial. The reaction was quenched by HCl (1 M, 10 mL), and wasextracted with DCM (10 mL×2). The combined organic layers were driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column (20 g) withEtOAc/Heptanes (10% to 80%) to afford tert-butylN-[1,1-dimethyl-2-oxo-2-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]ethyl]carbamate(159 mg, 78% yield) as a yellow liquid. LC-MS calc. for C₃₆H₄₉ClN₃O₇S[M+H]⁺: m/z=702.3/704.3; Found: 702.0/704.3.

Step 3:2-amino-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide

tert-ButylN-[1,1-dimethyl-2-oxo-2-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]ethyl]carbamate(230 mg, 0.33 mmol) was treated with 2M HCl in EA (10.0 mL, 0.33 mmol)at r.t. for 2 h. The solvent was evaporated under reduced pressure toafford the crude product as HCl salt which was used in next step withoutfurther purification. LC-MS calc. for C₃₁H₄₁ClN₃O₅S [M+H]⁺:m/z=602.2/604.2; Found: 602.0/604.2.

Step 4:2-(allylamino)-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide

To a stirred solution of2-amino-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamidehydrochloride (180 mg, 0.28 mmol) in DMF (5 mL) was added sodium hydride(45 mg, 1.13 mmol). The resulting mixture was stirred at r.t. for 5 min.Then allyl bromide (0.02 mL, 0.28 mmol) was added. The reaction wasstirred at r.t. for 48 h. LC-MS showed unreacted starting material(˜15%), desired product (˜60%) and dialkylation product (25%). Thereaction was quenched by adding water (20 mL). EtOAc (20 mL) was addedand the layers were separated. The organic layer was washed with water(20 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure The residue was purified by flash chromatography on asilica gel column (20 g) with EtOAc/Heptanes (30% to 100%) to afford2-(allylamino)-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide(57.5 mg, 31.7% yield) as a white solid. LC-MS calc. for C₃₄H₄₅ClN₃O₅S[M+H]⁺: 642.3/644.3; Found: 642.5/644.2.

Step 5:(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 4 using2-(allylamino)-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide.LC-MS calc. for C₃₂H₄₁ClN₃O₅S [M+H]⁺: 614.2/616.2; Found: 614.3/616.3.

Step 6:(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one.LC-MS calc. for C₃₃H₄₃ClN₃O₅S [M+H]⁺: m/z=628.3/630.3; Found:628.0/630.2. ¹H NMR (600 MHz, DMSO-d₆) δ 9.13 (s, 1H), 7.64 (d, J=8.5Hz, 1H), 7.25 (dd, J=8.5, 2.4 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 7.10 (d,J=8.2 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.74-6.70 (m, 1H), 6.27 (dd,J=12.4, 6.4 Hz, 1H), 5.62-5.57 (m, 1H), 4.04-3.95 (m, 2H), 3.56 (d,J=14.5 Hz, 1H), 3.53-3.37 (m, 2H), 3.21 (s, 3H), 3.01 (dd, J=15.2, 11.0Hz, 1H), 2.80 (dt, J=17.0, 4.3 Hz, 1H), 2.71 (ddd, J=16.8, 10.4, 6.5 Hz,1H), 2.65-2.55 (m, 2H), 2.49-2.25 (m, 3H), 2.03-1.90 (m, 3H), 1.87-1.81(m, 1H), 1.77-1.70 (m, 2H), 1.54-1.31 (m, 4H), 1.31-1.04 (m, 6H).

Example 43(3R,6R,7S,8E,22S)-6′-Chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: 3-allyl-4,4-dimethyl-oxazolidine-2,5-dione

To a solution of 2-[allyl(tert-butoxycarbonyl)amino]-2-methyl-propanoicacid (4.79 g, 19.6 mmol, Example 83 Step 1) in ethyl acetate (25 mL) wasadded t-butylchlorodiphenylsilane (3.26 g, 21.6 mmol) at 0° C. followedby addition of triethylamine (TEA) (2.74 mL, 19.6 mmol). Whiteprecipitate was formed immediately. The reaction was stirred at 0° C.for 30 min. The white solid was filtered off and rinsed with EtOAc. Thefiltrate was concentrated under reduced pressure. The residue wasdissolved in DCM (25 mL) and followed by addition of oxalyl chloride(2.1 mL, 24 mmol) and DMF (10 drops). Gas was evolved and the reactionwas stirred at r.t. overnight. TLC showed a new spot (R_(f)=0.6,EA:Heptane=1:1) formed. The reaction was concentrated and co-evaporatedTHF 3 times to remove excess oxalyl chloride. The residue was treatedwith THF (30 mL) and filtered to provide a stock solution of the desiredproduct (about 0.66 M with 98.6% purity showed by GC at 8.93 min.) whichwas directly used in next step reaction without further purification.

Step 2:2-(allylamino)-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide

To a solution of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(500.0 mg, 0.99 mmol, Intermediate 3) and3-allyl-4,4-dimethyl-oxazolidine-2,5-dione (3.01 mL, 1.99 mmol) in THF(5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (298 μL, 1.99 mmol).The resulting mixture was heated to 65° C. for 2 h. The reaction wascooled to r.t. Methanol (8 mL) and water (8 mL) were added, followed byaddition of lithium hydroxide monohydrate (500 mg, 11.9 mmol). Thereaction was heated to 45° C. for 3 h. THF was removed under reducedpressure. The residue was re-dissolved in DCM, and was quenched withsat. NH₄Cl aq. (5 mL). The mixture was extracted with DCM (5 mL×2). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column (20 g) with EtOAc/Heptanes (20% to100%) then MeOH/EtOAc (0% to 50%) to afford2-(allylamino)-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide(490 mg, 78.5% yield). LC-MS calc. for C₃₃H₄₃ClN₃O₅S [M+H]⁺:m/z=628.3/630.3; Found: 628.8/630.8.

Step 3:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 4 using2-(allylamino)-2-methyl-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-propanamide.LC-MS calc. for C₃₁H₃₉ClN₃O₅S [M+H]⁺: m/z=600.2/602.2; Found:600.7/602.7.

Step 4:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-oneand formaldehyde aqueous solution. LC-MS calc. for C₃₂H₄₁ClN₃O₅S [M+H]⁺:m/z=614.24/616.24; Found: 614.8/616.8. ¹H NMR (600 MHz, DMSO-d₆) δ 7.63(d, J=8.6 Hz, 1H), 7.25 (dd, J=8.5, 2.4 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H),7.14-7.10 (m, 1H), 7.08 (br, 1H), 6.86-6.84 (m, 2H), 5.79-5.73 (m, 1H),5.37-5.31 (m, 1H), 4.09 (d, J=19.1 Hz, 1H), 3.51 (d, J=14.6 Hz, 1H),3.07 (t, J=12.7 Hz, 1H), 2.84-2.76 (m, 1H), 2.71 (ddd, J=16.8, 10.8, 6.1Hz, 1H), 2.64-2.60 (m, 1H), 2.17 (d, J=11.4 Hz, 1H), 2.04-2.00 (m, 2H),1.89-1.82 (m, 3H), 1.67-1.61 (m, 2H), 1.47-1.41 (m, 3H), 1.35-1.33 (m,2H), 1.27-1.22 (m, 10H), 0.89-0.81 (m, 2H).

Example 44[(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43) and N,N-dimethylcarbamoyl chloride. LC-MS calc. forC₃₅H₄₆ClN₄O₆S [M+H]⁺: m/z=685.3/687.3; Found: 685.3/687.3. ¹H NMR (400MHz, DMSO-d₆) δ 9.02 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5,2.4 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H), 7.10 (dd, J=8.1, 1.9 Hz, 1H), 6.84(d, J=8.2 Hz, 1H), 6.77-6.73 (m, 1H), 6.62-6.59 (m, 1H), 6.29-6.26 (m,1H), 5.91-5.83 (m, 1H), 4.15-3.92 (m, 3H), 3.56 (d, J=14.6 Hz, 1H), 3.29(d, J=14.4 Hz, 2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.75-2.65 (m, 2H),2.57-2.51 (m, 4H), 2.43-2.26 (m, 3H), 2.08-1.79 (m, 4H), 1.68 (dt,J=17.5, 8.3 Hz, 2H), 1.57 (t, J=9.0 Hz, 2H), 1.36 (s, 3H), 1.18 (s, 3H).

Example 45[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-11-(trideuteriomethyl)spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

Step 1:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-11-(trideuteriomethyl)spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

To solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(425 mg, 0.71 mmol, Example 43) in DCE (10 mL) was added formaldehyde-d2solution (˜20 wt. % in D20) (113 mg, 3.54 mmol). The mixture was stirredat 20° C. for 2 h. LC-MS analysis indicated the starting material wasconsumed and the iminium intermediate was formed. Sodiumcyanoborodeuteride (233 mg, 3.54 mmol) was then added the reaction wasstirred for 4 h. LC-MS analysis indicated the reaction was complete. Thereaction was quenched with 1M HCl aq. solution (20 mL), and extractedwith DCM (20 mL×2). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-11-(trideuteriomethyl)spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(393 mg, 89.9% yield) as a light brown colored solid. LC-MS: calc. forC₃₂H₃₈D3ClN₃O₅S [M+H]⁺: m/z=617.26/619.26; Found: 617.3/619.1.

Step 2:[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-11-(trideuteriomethyl)spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-11-(trideuteriomethyl)spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-oneand N,N-dimethylcarbamoyl chloride. LC-MS calc. for C₃₅H₄₃ClD₃N₃O₆S[M+H]⁺: m/z=688.29/690.29; Found 688.5/690.3. ¹H NMR (499 MHz, DMSO-d₆)δ 7.62 (d, J=8.6 Hz, 1H), 7.23 (dd, J=8.5, 2.4 Hz, 1H), 7.15 (d, J=2.4Hz, 1H), 7.09 (dd, J=8.1, 1.9 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.75 (s,1H), 6.23 (s, 1H), 5.82 (d, J=15.8 Hz, 1H), 5.22 (s, 1H), 3.98 (q,J=12.2 Hz, 2H), 3.54 (d, J=14.5 Hz, 2H), 3.40 (t, J=11.6 Hz, 3H), 3.06(dd, J=15.1, 10.8 Hz, 1H), 3.00 (s, 3H), 2.84 (s, 3H), 2.78 (dt, J=16.8,4.5 Hz, 1H), 2.69 (ddd, J=16.4, 10.6, 5.9 Hz, 2H), 2.39-2.28 (m, 1H),2.02-1.93 (m, 1H), 1.93-1.76 (m, 3H), 1.68 (dt, J=17.7, 8.4 Hz, 2H),1.63-1.52 (m, 1H), 1.47-1.36 (m, 1H), 1.34 (s, 3H), 1.16 (s, 3H).

Example 46[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-(2-methoxyethyl)piperazine-1-carboxylate

Step 1: phenyl[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]carbonate

To a solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(2.8 g, 4.66 mmol, Example 32) and phenyl chloroformate (3.64 g, 23.2mmol) in ACN (60 mL) was added pyridine (3.77 mL, 46.5 mmol). Themixture was stirred at r.t. for 1 h. The reaction was monitored byLC-MS. The mixture was carefully neutralized with 0.5 N HCl (80 mL), andextracted with ethyl acetate (40 mL×2). The organic layer was washedwith saturated NaHCO₃(80 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with EtOAc/10% DCM in Heptanes(5-65%) to afford the desired product phenyl[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.0-3,6.0-19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]carbonate (1.24 g, 36.9% yield). LC-MS calc. for C₃₈H₄₂ClN₂O₈S [M+H]⁺:m/z=721.23.21/723.23; Found 721.8/723.8.

Step 2:[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.0˜3,6.0˜19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-(2-methoxyethyl)piperazine-1-carboxylate

To a solution of phenyl[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]carbonate (20.0 mg, 0.03 mmol) in MeCN (0.50 mL) was added1-(2-methoxyethyl)piperazine (12.0 mg, 0.08 mmol). The reaction washeated to 80° C. for 2 h. The reaction was cooled to r.t. andconcentrated under reduced pressure. The residue was re-dissolved in DCM(2 mL) and washed with 0.5 N HCl aq. (2 mL). Aqueous layer was extractedwith DCM (2 mL) one more time. The combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The residue was purified by prep-HPLC on C18 column (21.2×150mm, 5 m) using MeCN/H₂O (20% to 100% over 18 min) to afford[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-(2-methoxyethyl)piperazine-1-carboxylate (10.6 mg, 48.7% yield). LC-MScalc. for C₃₉H₅₂ClN₄O₈S [M+H]⁺: m/z=771.32/773.32; Found: 771.8/773.8.¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.1Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 7.02-6.95(m, 2H), 5.88-5.75 (m, 1H), 5.70 (dd, J=15.7, 4.9 Hz, 1H), 5.34 (s, 1H),4.11 (dt, J=11.6, 9.0 Hz, 3H), 3.81-3.65 (m, 3H), 3.62-3.43 (m, 5H),3.43-3.31 (m, 4H), 3.22 (dd, J=15.1, 9.1 Hz, 1H), 2.85-2.67 (m, 2H),2.60 (t, J=5.5 Hz, 3H), 2.38 (d, J=3.8 Hz, 2H), 2.08-1.89 (m, 5H),1.89-1.71 (m, 4H), 1.63 (t, J=9.4 Hz, 2H), 1.50 (d, J=12.5 Hz, 2H), 1.44(s, 3H), 1.37 (s, 3H).

Example 47[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-bis(trideuteriomethyl)carbamate

To a solution of DIPEA (232 mg, 1.8 mmol) in MeCN (3 mL) was added1,1,1-trideuterio-N-(trideuteriomethyl)methanamine hydrochloride (0.3mL, 1.8 mmol). The resulting mixture was stirred for 5 min at r.t.[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]phenyl carbonate (260 mg, 0.36 mmol, Example 46 Step 1) was then addedto the reaction mixture and the resulting solution was stirred at 65° C.for 4 h. LCMS analysis indicated the reaction was complete. The reactionmixture was concentrated under reduced pressure and the residue waspurified by prep-HPLC. The desired fractions were collected andconcentrated under reduced pressure to afford[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-bis(trideuteriomethyl)carbamate (202 mg, 82.6% yield) as a whitesolid. LC-MS: calc. for C₃₄H₃₆D6ClN₃O₇S [M+H]⁺: m/z=678.3/680.3; Found678.4/680.4. ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 7.68 (d, J=8.5 Hz,1H), 7.50 (dd, J=8.3, 2.2 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.10(d, J=2.3 Hz, 1H), 7.02-6.94 (m, 2H), 5.97-5.58 (m, 2H), 5.30 (d, J=5.0Hz, 1H), 4.17-4.04 (m, 3H), 3.79-3.63 (m, 3H), 3.50-3.32 (m, 2H), 3.19(dd, J=14.5, 4.9 Hz, 1H), 2.78 (t, J=5.5 Hz, 3H), 2.38 (qd, J=9.0, 3.6Hz, 1H), 2.06-1.90 (m, 3H), 1.83 (q, J=8.9 Hz, 3H), 1.64 (p, J=9.7 Hz,1H), 1.45 (s, 3H), 1.37 (s, 3H).

Example 48[(3R,6R,7R,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

Step 1:(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a stirred solution of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(300 mg, 0.60 mmol) in DMF (3 mL) was added TBSCl (269 mg, 1.79 mmol)followed by imidazole (243 mg, 3.58 mmol). The resulting mixture wasstirred at r.t. for 4 h. HCl (aq, 0.5 M, 10 mL) was added followed by 10mL of EtOAc. The layers were separated, and the organic layer was washedwith 10 mL of HCl (0.5 M). The organic layer was dried over sodiumsulfate and concentrated under reduced pressure The residue was purifiedby flash chromatography on a silica gel column (12 g) using 2% to 35%EtOAc/Heptanes. The desired fractions were collected to afford(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(260 mg, 70% yield) as a white solid. LC-MS calc. for C₃₂H₄₆ClN₂O₄SiS[M+H]⁺: m/z=617.3/619.3; Found: 617.8/619.4.

Step 2: tert-butylN-allyl-N-[1-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]cyclobutyl]carbamate

To a stirred solution of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(260 mg, 0.42 mmol) in DCM (10 mL) was added1-[allyl(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid (322 mg,1.26 mmol), 4-(dimethylamino)pyridine (308 mg, 2.53 mmol) and EDCI (0.25mL, 1.26 mmol) successively. The resulting mixture was stirred at r.t.for 48 hours. HCl (1 M, 30 mL) was added followed by 30 mL of DCM. Thelayers were separated, and the aqueous layer was extracted with DCM. Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure The residue was purified by flash chromatographyon a silica gel column (12 g) using EtOAc/Heptanes (5% to 80%). Thedesired fractions were collected to afford tert-butylN-allyl-N-[1-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]cyclobutyl]carbamate(190 mg, 53% yield) as a white solid. LC-MS calc. for C₄₅H₆₅ClN₃O₇SiS[M+H]⁺: m/z=854.4/856.4; Found: 855.0/857.1.

Step 3: tert-butylN-allyl-N-[1-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]cyclobutyl]carbamate

A solution of tert-butylN-allyl-N-[1-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]cyclobutyl]carbamate(190 mg, 0.22 mmol) in THF (3 mL) and tetrabutylammonium fluoridesolution (3.0 mL, 0.22 mmol, 1 M in THF) was stirred at r.t. overnight.The reaction was quenched by adding 10 mL of saturated NH₄Cl solutionfollowed by 10 mL of EtOAc. The layers were separated and the aqueouslayer was extracted with EtOAc (10 mL×3). The combined organic layerswere washed with brine, dried over sodium sulfate and concentrated underreduced pressure The residue was purified by flash chromatography on asilica gel column (20 g) using 10% to 100% EtOAc/Heptanes then 0% to 50%MeOH/EtOAc. The desired fractions were collected to afford tert-butylN-allyl-N-[1-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]cyclobutyl]carbamate(101 mg, 61% yield) as a white solid. LC-MS: calcd. For C₃₉H₅₁ClN₃O₇S[M+H]⁺: m/z=740.3/742.3; Found: 740.8/743.0.

Step 4:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-tert-butoxycarbonyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

To a stirred solution of tert-butylN-allyl-N-[1-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylcarbamoyl]cyclobutyl]carbamate(60 mg, 0.08 mmol) in DCE (80 mL) was bubbled with nitrogen for 20minutes. Then1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (resin supported)Zhan Catalyst II (11.8 mg, 0.02 mmol) was added under nitrogen. Theresulting mixture was further bubbled with nitrogen for 20 minutes. Thenthe reaction was stirred at 60° C. under nitrogen for 3 hours. LC-MSshowed the consumption of the starting material and the formation ofdesired product. The reaction was cooled to r.t. and stirred under airfor 30 minutes to deactivate the catalyst. The solution was concentratedunder reduced pressure. The residue was purified by flash chromatographyon a silica gel column (12 g) using 20% to 100% EtOAc/Heptanes. Thedesired fractions were collected to afford(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-tert-butoxycarbonyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(54 mg, 93% yield) as a white solid. LC-MS calc. for C₃₇H₄₇ClN₃O₇S[M+H]⁺: m/z=712.3/714.3; Found: 712.9/714.6.

Step 5:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

To a stirred solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-tert-butoxycarbonyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(45.0 mg, 0.06 mmol) in DCM (3 mL) was added phosphoric acid (3.0 mL,43.8 mmol). The resulting mixture was stirred at r.t. for 48 h. Thesolution was slowly poured into saturated NaHCO₃solution (20 mL) underan ice bath. The mixture was extracted with DCM (10 mL×3). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure The crude product(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(37 mg, quantitative yield) was used in next step without furtherpurification. LC-MS calc. for C₃₂H₃₉ClN₃O₅S [M+H]⁺: m/z=612.2/614.2;Found: 612.8/614.6.

Step 6:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one.LC-MS calc. for C₃₃H₄₁ClN₃O₅S [M+H]⁺: m/z=626.2/628.2; Found:626.9/628.8. ¹H NMR (499 MHz, DMSO-d₆) δ 7.61 (d, J=8.5 Hz, 1H), 7.23(dd, J=8.5, 2.4 Hz, 1H), 7.20 (dd, J=8.2, 2.0 Hz, 1H), 7.18 (d, J=2.4Hz, 1H), 6.99-6.95 (m, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.64-5.56 (m, 1H),4.84-4.77 (m, 1H), 4.06 (d, J=12.1 Hz, 1H), 4.00-3.84 (m, 2H), 3.49 (d,J=14.3 Hz, 1H), 2.89-2.57 (m, 6H), 2.39-2.21 (m, 4H), 2.07-1.96 (m, 2H),1.86-1.77 (m, 6H), 1.70-1.64 (m, 1H), 1.61-1.54 (m, 2H), 1.47 (q, J=7.2Hz, 1H), 1.30-1.23 (m, 5H), 0.89-0.84 (m, 1H).

Step 7:[(3R,6R,7R,8E,22S)-6′-Chloro-1-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-oneand N,N-dimethylcarbamoyl chloride. LC-MS calc. for C₃₆H₄₆ClN₄O₆S[M+H]⁺: m/z=697.3/699.3; Found: 697.9/699.7. ¹H NMR (300 MHz, CDCl₃) δ7.67 (d, J=8.5 Hz, 1H), 7.49 (dd, J=8.3, 2.1 Hz, 1H), 7.16 (dd, J=8.5,2.3 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.85 (d,J=2.3 Hz, 1H), 5.79-5.59 (m, 2H), 5.28 (s, 1H), 4.29-3.97 (m, 2H), 3.70(d, J=14.7 Hz, 1H), 3.53-3.26 (m, 2H), 3.04 (s, 3H), 2.95 (s, 3H),2.89-2.57 (m, 6H), 2.40 (s, 3H), 2.27 (ddt, J=11.9, 8.2, 3.2 Hz, 2H),2.19-1.90 (m, 7H), 1.87-1.73 (m, 3H), 1.73-1.55 (m, 3H), 1.41 (t, J=11.8Hz, 1H).

Example 49[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3,3-difluoroazetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 3,3-difluoroazetidine hydrochloride andN,N-diisopropylethylamine to replace 1-(2-methoxyethyl)piperazine inStep 2. LC-MS calc. for C₃₅H₄₁ClF₂N₃O₇S [M+H]⁺: m/z=720.22/722.22; Found720.8/722.89. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.50 (d,J=8.2 Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H),7.05-6.94 (m, 2H), 5.82 (m, 1H), 5.71 (m, 1H), 5.28 (s, 1H), 4.32 (m,2H), 4.18-4.05 (m, 3H), 3.81-3.68 (m, 2H), 3.47-3.32 (m, 2H), 3.23 (m,1H), 2.85-2.69 (m, 3H), 2.46-2.35 (m, 1H), 2.01 (m, 3H), 1.90-1.76 (m,4H), 1.71-1.58 (m, 3H), 1.46-1.58 (m, 1H), 1.45 (s, 3H), 1.37 (s, 3H).

Example 50[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using methylamine to replace 1-(2-methoxyethyl)piperazinein Step 2. LC-MS calc. for C₃₃H₄₁ClN₃O₇S [M+H]⁺: m/z=658.23/660.23;Found 658.7/660.7. ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H),7.51 (dd, J=8.3, 1.9 Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (d,J=2.1 Hz, 1H), 7.08-7.02 (m, 1H), 7.00 (d, J=8.3 Hz, 1H), 5.88-5.65 (m,2H), 5.24 (s, 1H), 4.86 (s, 1H), 4.20-4.05 (m, 3H), 3.74 (m, 2H), 3.47(dd, J=15.1, 4.8 Hz, 1H), 3.34 (d, J=14.6 Hz, 1H), 3.17 (m, 1H), 2.80(m, 6H), 2.42-2.32 (m, 1H), 1.98 (m, 4H), 1.81 (m, 3H), 1.64 (m, 2H),1.44 (s, 3H), 1.38 (s, 3H).

Example 51(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-methoxypiperidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 4-methoxypiperidine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₈₃H₄₉ClN₃O₈S[M+H]⁺: m/z=742.29/744.29; Found: 742.7/744.8. ¹H NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.19 (dd,J=8.5, 2.2 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 6.99 (d, J=8.2 Hz, 2H), 5.73(t, J=20.2 Hz, 2H), 5.32 (d, J=3.8 Hz, 1H), 4.22-3.98 (m, 3H), 3.92-3.64(m, 5H), 3.51-3.29 (m, 6H), 3.22 (dd, J=14.5, 8.9 Hz, 4H), 2.79 (d,J=4.1 Hz, 3H), 2.39 (d, J=6.8 Hz, 1H), 2.10-1.46 (m, 10H), 1.44 (s, 3H),1.37 (s, 3H).

Example 52[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-(dimethylamino)azetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using N,N-dimethylazetidin-3-amine dihydrochloride saltand Hunig's base to replace 1-(2-methoxyethyl)piperazine in Step 2.LC-MS calc. for C₃₇H₄₈ClN₄O₇S [M+H]⁺: m/z=727.3/729.3; Found:727.6/729.6. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.51-7.40(m, 1H), 7.18 (dd, J=8.5, 2.3 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.96 (d,J=8.3 Hz, 1H), 5.81-5.59 (m, 1H), 5.15 (s, 1H), 4.29 (s, 1H), 4.11 (q,J=11.4, 10.7 Hz, 4H), 3.85 (dd, J=9.1, 4.9 Hz, 2H), 3.71 (d, J=14.6 Hz,2H), 3.40 (t, J=17.2 Hz, 2H), 2.97 (s, 5H), 2.80 (s, 3H), 2.21 (s, 6H),1.99 (d, J=16.0 Hz, 3H), 1.90-1.73 (m, 3H), 1.73-1.58 (m, 2H), 1.46 (s,3H), 1.34 (s, 3H).

Example 53[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-(dimethylamino)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3R)—N,N-dimethylpyrrolidin-3-amine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₃₈H₅₀ClN₄O₇S[M+H]⁺: m/z=741.3/743.3; Found: 741.4/743.2. ¹H NMR (499 MHz, DMSO-d₆) δ7.67 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.4, 2.3 Hz, 1H), 7.18 (d, J=2.4 Hz,1H), 7.11 (dd, J=8.1, 1.9 Hz, 1H), 6.92-6.80 (m, 2H), 6.23 (dd, J=16.5,7.7 Hz, 1H), 5.54 (dd, J=16.0, 4.1 Hz, 1H), 5.10 (d, J=40.1 Hz, 1H),4.02 (d, J=7.7 Hz, 3H), 3.88 (dd, J=13.5, 8.0 Hz, 1H), 3.57 (dt, J=12.3,4.5 Hz, 4H), 3.34-3.26 (m, 4H), 3.08 (td, J=15.2, 9.8 Hz, 2H), 2.75(dddd, J=33.6, 16.8, 11.5, 5.3 Hz, 3H), 2.39 (d, J=23.1 Hz, 6H),2.16-1.76 (m, 6H), 1.74-1.56 (m, 3H), 1.49-1.36 (m, 1H), 1.23 (d, J=2.4Hz, 3H), 1.12 (s, 3H).

Example 54[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-methyl-1,4-diazepane-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 1-methyl-1,4-diazepane to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₃₈H₅₀ClN₄O₇S[M+H]⁺: m/z=741.3/743.3; Found: 741.4/743.2. ¹H NMR (300 MHz, CDCl₃) δ7.69 (dd, J=8.5, 3.6 Hz, 1H), 7.54-7.37 (m, 1H), 7.18 (dd, J=8.5, 2.3Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 7.02-6.84 (m, 2H), 6.26-5.60 (m, 1H),5.28 (s, 1H), 4.31 (d, J=12.4 Hz, 1H), 4.21-3.96 (m, 4H), 3.72 (d,J=14.5 Hz, 2H), 3.52-3.01 (m, 10H), 2.92-2.48 (m, 8H), 2.43 (s, 1H),2.24 (t, J=9.9 Hz, 1H), 2.06-1.75 (m, 7H), 1.42 (s, 3H), 1.34 (s, 3H).

Example 55[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.0-3,6.0-19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[2-(dimethylamino)ethyl]-N-methyl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using N,N,N′-trimethylethylenediamine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₃₇H₅₀ClN₄O₇S[M+H]⁺: m/z=729.31/731.31; Found: 729.5/731.5. ¹H NMR (500 MHz, DMSO-d₆)δ 11.62 (s, 1H), 9.39 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.26 (dd, J=8.5,2.3 Hz, 2H), 7.19 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.94 (s,1H), 6.59 (d, J=61.5 Hz, 1H), 5.71 (s, 2H), 5.24 (d, J=88.7 Hz, 1H),4.34-3.89 (m, 3H), 3.56 (d, J=14.4 Hz, 2H), 3.02-2.62 (m, 13H),2.12-1.44 (m, 10H), 1.39 (s, 3H), 1.24 (s, 6H).

Example 56[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-methoxyazetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 3-methoxyazetidine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₃₆H₄₅ClN₃O₈S[M+H]⁺: m/z=714.25/716.25; Found: 714.5/716.5. ¹H NMR (499 MHz, DMSO-d₆)δ 7.71 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 2.5 Hz, 1H), 7.21 (d, J=2.4Hz, 1H), 7.12 (dd, J=8.2, 1.9 Hz, 1H), 6.94-6.80 (m, 2H), 6.30 (d,J=12.0 Hz, 1H), 5.51 (ddd, J=16.0, 3.7, 1.7 Hz, 1H), 5.05 (s, 1H), 4.25(s, 1H), 4.17-4.10 (m, 1H), 4.08-3.99 (m, 2H), 3.87 (dd, J=13.5, 7.8 Hz,1H), 3.78 (d, J=7.9 Hz, 1H), 3.65-3.53 (m, 2H), 3.38 (s, 2H), 3.32 (d,J=14.3 Hz, 2H), 3.26 (s, 3H), 3.10 (dd, J=14.9, 10.1 Hz, 1H), 2.89-2.67(m, 3H), 2.33 (td, J=8.8, 2.8 Hz, 1H), 2.06-1.97 (m, 1H), 1.92-1.83 (m,3H), 1.69 (ddt, J=17.6, 12.7, 8.1 Hz, 3H), 1.47 (td, J=13.2, 12.1, 3.9Hz, 1H), 1.30 (s, 1H), 1.24 (s, 3H), 1.13 (s, 3H).

Example 57[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-ethoxyazetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 3-ethoxyazetidine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₃₇H₄₇ClN₃O₈S[M+H]⁺: m/z=728.27/730.27; Found: 728.5/730.5. ¹H NMR (499 MHz, DMSO-d₆)δ 7.66 (d, J=8.6 Hz, 1H), 7.25 (dd, J=8.5, 2.4 Hz, 1H), 7.16 (d, J=2.4Hz, 1H), 7.06 (dd, J=8.1, 1.9 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 6.79 (d,J=8.1 Hz, 1H), 6.24 (d, J=13.1 Hz, 1H), 5.46 (dt, J=16.1, 2.9 Hz, 1H),5.00 (s, 1H), 4.28 (q, J=5.3 Hz, 1H), 4.09 (dd, J=9.3, 6.5 Hz, 2H),4.03-3.93 (m, 2H), 3.85-3.64 (m, 3H), 3.60-3.47 (m, 2H), 3.39 (d, J=6.9Hz, 1H), 3.26 (d, J=14.3 Hz, 2H), 3.04 (dd, J=14.8, 10.1 Hz, 1H),2.86-2.60 (m, 3H), 2.28 (qd, J=9.2, 3.0 Hz, 1H), 2.03-1.91 (m, 1H),1.88-1.75 (m, 3H), 1.71-1.56 (m, 3H), 1.41 (td, J=13.1, 12.2, 4.3 Hz,1H), 1.30-1.21 (m, 1H), 1.18 (s, 3H), 1.13 (t, J=7.5 Hz, 3H), 1.08 (s,3H).

Example 58[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-methoxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3R)-3-methoxypyrrolidine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₃₇H₄₇ClN₃O₈S[M+H]⁺: m/z=728.27/730.27; Found: 728.5/730.5. ¹H NMR (300 MHz, CDCl₃) δ7.68 (d, J=8.5 Hz, 1H), 7.37 (dd, J=8.3, 1.9 Hz, 1H), 7.13 (dd, J=8.4,2.3 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.96 (t, J=3.1 Hz, 1H), 6.87 (dd,J=8.3, 3.2 Hz, 1H), 6.08 (d, J=23.0 Hz, 1H), 5.69 (dt, J=15.3, 6.5 Hz,1H), 5.19 (d, J=15.8 Hz, 1H), 4.08-3.92 (m, 3H), 3.82 (d, J=6.9 Hz, 1H),3.69-3.58 (m, 2H), 3.48 (dt, J=19.4, 8.9 Hz, 3H), 3.35-3.24 (m, 4H),3.17-3.05 (m, 2H), 2.75 (s, 3H), 2.56 (q, J=7.2 Hz, 1H), 2.31 (t, J=9.7Hz, 1H), 2.01-1.89 (m, 3H), 1.78 (s, 3H), 1.60 (t, J=9.1 Hz, 1H),1.39-1.30 (m, 10H).

Example 59[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-ethoxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3R)-3-ethoxypyrrolidine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₈₃H₄₉ClN₃O₈S[M+H]⁺: m/z=742.29/744.28; Found: 742.6/744.6. ¹H NMR (300 MHz, CDCl₃) δ7.69 (d, J=8.5 Hz, 1H), 7.37-7.28 (m, 1H), 7.12 (dd, J=8.4, 2.3 Hz, 1H),7.06 (d, J=2.2 Hz, 1H), 7.00 (d, J=3.4 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H),6.34-6.07 (m, 1H), 5.70 (dt, J=15.5, 8.1 Hz, 1H), 5.13 (s, 1H),4.07-3.86 (m, 4H), 3.67-3.38 (m, 7H), 3.22 (d, J=14.4 Hz, 1H), 3.05 (p,J=8.8 Hz, 1H), 2.76-2.74 (m, 2H), 2.68-2.50 (m, 1H), 2.23-2.19 (m, 6H),2.02-1.70 (m, 8H), 1.63-1.53 (m, 1H), 1.35-1.25 (m, 8H).

Example 60[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-(2-methoxyethyl)-1,4-diazepane-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 1-(2-methoxyethyl)-1,4-diazepane to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₄₀H₅₄ClN₄O₈S[M+H]⁺: m/z=785.33/787.32; Found: 785.5/787.4; ¹H NMR (300 MHz, CDCl₃) δ9.29 (s, 1H, NH), 7.68 (dd, J=8.5, 5.1 Hz, 1H), 7.47 (dd, J=7.1, 5.2 Hz,1H), 7.19 (d, J=8.4 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.3 Hz,1H), 6.87 (d, J=10.0 Hz, 1H), 5.90 (s, 2H), 5.27 (s, 1H), 4.13 (m, 4H),3.75 (m, 9H), 3.47 (d, J=15.0 Hz, 2H), 3.35 (d, J=12.2 Hz, 6H),3.25-3.16 (m, 2H), 2.79 (d, J=4.2 Hz, 4H), 2.36 (d, J=8.0 Hz, 2H), 1.98(d, J=11.1 Hz, 2H), 1.91-1.76 (m, 4H), 1.76-1.63 (m, 2H), 1.46 (s, 3H),1.36 (d, J=2.4 Hz, 3H).

Example 61[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[(3S)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3S)-tetrahydrofuran-3-amine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₃₆H₄₅ClN₃O₈S[M+H]⁺: m/z=714.2; Found: 714.4. ¹H NMR (300 MHz, CDCl₃) δ 9.85 (s, 1H),7.68 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5,2.4 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 7.00 (d, J=8.4 Hz, 2H), 6.02 (m,1H), 5.65 (m, 2H), 5.17 (s, 1H), 4.27 (m, 2H), 4.21-4.03 (m, 2H), 3.99(d, J=9.7 Hz, 1H), 3.81-3.59 (m, 6H), 3.47-3.28 (m, 2H), 3.08 (dd,J=15.0, 10.2 Hz, 1H), 2.96-2.69 (m, 3H), 2.37-2.19 (m, 2H), 1.93 (m,7H), 1.67-1.54 (m, 1H), 1.47 (s, 3H), 1.34 (s, 3H).

Example 62[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[(3R)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3R)-tetrahydrofuran-3-amine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₃₆H₄₅ClN₃O₈S[M+H]⁺: m/z=714.2; Found: 714.4. ¹H NMR (300 MHz, CDCl₃) δ 9.08 (s, 1H),7.68 (d, J=8.5 Hz, 1H), 7.51 (dd, J=8.3, 2.0 Hz, 1H), 7.19 (dd, J=8.5,2.4 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.07-6.96 (m, 2H), 5.87-5.61 (m,2H), 5.18 (s, 1H), 4.36-4.01 (m, 6H), 3.97 m, 1H), 3.91-3.66 (m, 5H),3.47 (dd, J=15.3, 5.0 Hz, 1H), 3.33 (d, J=14.6 Hz, 1H), 3.18 (dd,J=15.2, 8.5 Hz, 1H), 2.78 (m, 3H), 2.48-2.34 (m, 1H), 2.32-2.19 (m, 1H),2.09-1.70 (m, 7H), 1.63 (t, J=9.4 Hz, 1H), 1.44 (s, 3H), 1.38 (s, 3H).

Example 63[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methoxy-N-methyl-carbamate

Step 1: N-methoxy-N-methyl-carbamoyl chloride

To a solution of N,O-dimethylhydroxylamine hydrochloride (500 mg, 8.19mmol) in DCM (10 mL) was added triphosgene (2429 mg, 8.19 mmol),followed by potassium carbonate (4525 mg, 32.7 mmol). The mixture wasstirred at r.t. for 1 h. NMR showed that the starting material wasconsumed. The reaction was then added H₂O (15 mL) and extracted with DCM(10 mL×3). The combined organic layers were dried over Na₂SO₄, filteredand concentrated under reduced pressure. The resulting residueN-methoxy-N-methyl-carbamoyl chloride (600 mg, 59% yield) was directlyused in the following step without further purification.

Step 2:[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methoxy-N-methyl-carbamate

To a solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(40.0 mg, 0.07 mmol, Example 32) and N-methoxy-N-methyl-carbamoylchloride (41 mg, 0.33 mmol) in toluene (2 mL) was dropwise added KHMDS(0.8 mL, 3.53 mmol) at −30° C. The mixture was then warmed to r.t. andstirred for 4 h. LC-MS showed that most of the starting material wasconsumed. The mixture was then added 1 N HCl (5 mL) and extracted withethyl acetate (5 mL×3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC on a C18 column using H₂O/ACN (20-100%) toafford the desired product[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methoxy-N-methyl-carbamate (19.7 mg, 43% yield). LC-MS calc. forC₃₄H₄₃ClN₃O₈S [M+H]⁺: m/z=688.24/690.24; Found: 688.4/690.5; ¹H NMR (300MHz, CDCl₃) δ 9.09 (s, 1H, NH), 7.69 (t, J=7.0 Hz, 1H), 7.51 (dd, J=8.3,2.0 Hz, 1H), 7.19 (dd, J=8.5, 2.0 Hz, 1H), 7.10 (d, J=1.9 Hz, 1H), 7.01(dd, J=8.7, 3.2 Hz, 2H), 5.90-5.79 (m, 1H), 5.70 (dd, J=15.6, 5.6 Hz,1H), 5.32 (d, J=4.0 Hz, 1H), 4.14 (q, J=12.2 Hz, 2H), 4.04 (dd, J=13.9,5.6 Hz, 1H), 3.77 (d, J=9.1 Hz, 1H), 3.72 (d, J=3.3 Hz, 4H), 3.44-3.34(m, 2H), 3.28 (dd, J=13.8, 7.7 Hz, 1H), 3.19 (s, 3H), 2.79 (d, J=4.6 Hz,3H), 2.49-2.39 (m, 1H), 2.00 (dd, J=11.5, 3.6 Hz, 2H), 1.84 (dd, J=16.9,8.9 Hz, 3H), 1.66-1.60 (m, 3H), 1.45-1.41 (s, 3H), 1.37 (s, 3H).

Example 64[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 32) in Step 2 and (3R)—N-methyltetrahydrofuran-3-aminehydrochloride in Step 1. LC-MS calc. for C₃₇H₄₇ClN₃O₈S [M+H]⁺:m/z=728.27/730.27; Found: 728.4/730.3. ¹H NMR (300 MHz, CDCl₃) δ 9.11(s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.2 Hz, 1H), 7.19 (dd,J=8.5, 2.4 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.96(d, J=2.3 Hz, 1H), 5.83 (d, J=4.3 Hz, 1H), 5.73 (dd, J=15.8, 5.3 Hz,1H), 5.35 (d, J=5.7 Hz, 1H), 4.93 (s, 1H), 4.14 (d, J=6.5 Hz, 2H), 4.08(d, J=5.4 Hz, 1H), 3.77 (d, J=5.1 Hz, 2H), 3.71 (s, 1H), 3.49-3.34 (m,2H), 3.23 (dd, J=15.1, 9.4 Hz, 1H), 2.92 (s, 3H), 2.83-2.75 (m, 3H),2.44-2.36 (m, 1H), 2.28-2.16 (m, 4H), 2.05-1.95 (m, 3H), 1.89-1.75 (m,4H), 1.65 (t, J=9.4 Hz, 2H), 1.44 (d, J=4.2 Hz, 3H), 1.37 (s, 3H).

Example 65(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(dimethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: ethyl2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyacetate

To a cooled (ice-bath) solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(1.0 g, 1.66 mmol, Example 32) in THF (10 mL) was added sodium hydride(199 mg, 8.32 mmol). After stirring 10 mins at r.t., ethyl bromoacetate(1111 mg, 6.65 mmol) was added. The resulting mixture was stirred atr.t. overnight. The reaction was monitored by LC-MS and quenched with amixture of cold 1 N HCl aq. (50 mL) and DCM (50 mL). The aqueous layerwas extracted with DCM (50 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column (20g) using EA/Heptane (5%-80%) to afford the desired product ethyl2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyacetate(600 mg, 52.4% yield). LC-MS calc. for C₃₅H₄₄ClN₂O₈S [M+H]⁺: m/z=687.20;Found: 687.72.

Step 2:2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyaceticacid

To a solution of ethyl2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyacetate(600 mg, 0.87 mmol) in THF (10 mL) and water (10 mL) was added lithiumhydroxide monohydrate (183.18 mg, 4.37 mmol). The mixture was stirred atr.t. for 1 h. The mixture was then was quenched with 1N HCl (50 mL),extracted with EA (50 mL×2). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]oxyaceticacid (400 mg, 70% yield) which was directly used in next step withoutpurification. LC-MS calc. for C₃₃H₄₀ClN₂O₆S [M+H]⁺: m/z=659.22; Found:659.70. 1H NMR (300 MHz, CDCl₃) δ 9.24 (s, 1H, NH), 7.64 (t, J=6.0 Hz,1H), 7.49 (dd, J=8.3, 2.0 Hz, 1H), 7.18 (dd, J=8.5, 2.2 Hz, 1H), 7.10(d, J=2.1 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 7.02-6.98 (m, 1H), 5.73-5.59(m, 2H), 4.15-4.03 (m, 4H), 3.94-3.83 (m, 3H), 3.68 (d, J=14.7 Hz, 1H),3.36 (dd, J=14.4, 8.5 Hz, 3H), 2.85-2.72 (m, 3H), 2.45-2.35 (m, 1H),2.02 (t, J=7.9 Hz, 3H), 1.95-1.75 (m, 3H), 1.64 (t, J=8.8 Hz, 1H), 1.54(d, J=11.7 Hz, 1H), 1.46-1.41 (m, 3H), 1.39 (s, 3H).

Step 3: isobutoxycarbonyl2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyacetate

To a solution2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyaceticacid (400 mg, 0.60 mmol) in THF (16 mL) cooled with an ice-bath wasadded triethylamine (0.33 mL, 2.38 mmol) and isobutyl chloroformate(0.27 mL, 2.09 mmol). The reaction mixture was stirred at r.t. for 60min. and monitored by LC-MS. When LC-MS shows complete reaction, thecrude was directly used in further step without work-up andpurification. LC-MS calc. for C₃₈H₄₈ClN₂O₁₀S [M+H]⁺: m/z=759.27; Found:759.87.

Step 4:2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyacetaldehyde

To a solution of isobutoxycarbonyl2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyacetate(456.0 mg, 0.60 mmol) in THF (16 mL) at −78° C. was addeddiisobutylaluminum hydride (4.0 mL, 6.0 mmol, 1.5 M in toluene). Thereaction was stirred for 30 mins at −78° C. The reaction mixture wasquenched with 10% Rochelle's salt aqueous solution (40 mL) and themixture was stirred at r.t. for 1 h. The layers were separated, and theaqueous layer was extracted with EA (2×50 mL). The combined organiclayers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure to afford2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyacetaldehyde(400 mg, 60%) which was directly used in next step without purification.LC-MS calc. for C₃₃H₄₀ClN₂O₆S [M+H]⁺: m/z=643.22; Found: 643.5.

Step 5:(3R,6R,7S,8E,22S)-6′-chloro-7-[2-(dimethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[1,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

To a solution of2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyacetaldehyde(235 mg, 0.37 mmol, 60%) in DCE (5 mL) was added dimethylamine in THF(750.0 μL, 1.5 mmol, 2.0 M THF solution). The mixture was stirred atr.t. for 5 min., followed by adding of sodium triacetoxyborohydride (316mg, 1.5 mmol). The mixture was then stirred at r.t. for additional 30min. LC-MS showed that the starting material was consumed. The reactionwas quenched by 1N HCl (10 mL) and extracted with DCM (2×10 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC on a C18 column using H₂O/ACN (20-100%) to afford the desiredproduct(3R,6R,7S,8E,22S)-6′-chloro-7-[2-(dimethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(73 mg, 46% yield). LC-MS calc. for C₃₅H₄₇ClN₃O₆S [M+H]⁺: m/z=672.28;Found: 672.4. ¹H NMR (300 MHz, DMSO-d₆) δ 9.42 (s, 1H, NH), 7.61 (d,J=8.5 Hz, 1H), 7.33-7.16 (m, 3H), 7.03 (t, J=7.5 Hz, 2H), 5.59 (dd,J=15.6, 6.7 Hz, 1H), 5.43 (d, J=14.1 Hz, 1H), 4.08 (dd, J=19.7, 12.1 Hz,2H), 3.91 (dd, J=14.3, 6.0 Hz, 1H), 3.67-3.60 (m, 2H), 3.32 (m, 5H),3.15 (dd, J=14.5, 7.5 Hz, 2H), 2.79 (s, 9H), 2.43 (d, J=8.5 Hz, 2H),1.97 (d, J=10.0 Hz, 1H), 1.86 (t, J=12.2 Hz, 4H), 1.71 (d, J=8.4 Hz,1H), 1.58 (d, J=9.0 Hz, 2H), 1.43-1.31 (m, 3H), 1.24 (s, 3H).

Example 66(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-15,15-dioxo-7-(2-pyrrolidin-1-ylethoxy)spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using pyrrolidine to replace dimethylamine in THF (2.0 M)in Step 5. LC-MS calc. for C₃₇H₄₉ClN₃O₆S [M+H]⁺: m/z=698.30/700.29;Found: 698.5/700.7; ¹H NMR (300 MHz, DMSO-d₆) δ 9.56 (s, 1H, NH),7.66-7.56 (m, 1H), 7.25 (m, 3H), 7.03 (dd, J=9.5, 6.1 Hz, 2H), 5.58 (dd,J=15.5, 6.9 Hz, 1H), 5.40 (d, J=13.6 Hz, 1H), 4.08 (dd, J=19.3, 12.1 Hz,2H), 3.88 (dd, J=14.4, 6.0 Hz, 1H), 3.66-3.58 (m, 2H), 3.32 (d, J=14.9Hz, 8H), 3.15 (dd, J=14.5, 7.9 Hz, 2H), 3.04 (s, 3H), 2.79-2.62 (m, 3H),1.97 (d, J=5.4 Hz, 3H), 1.87 (dd, J=18.6, 5.1 Hz, 6H), 1.72 (d, J=8.4Hz, 1H), 1.63-1.52 (m, 2H), 1.43-1.30 (m, 3H), 1.24 (s, 3H).

Example 67(3R,6R,7R,8E,23S)-6′-Chloro-7-methoxy-11-methoxycarbonyl-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one

To a solution of(3R,6R,7R,8E,23S)-6′-chloro-7-methoxy-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one(8.0 mg, 0.01 mmol, Example 26) and triethylamine (0.01 mL, 0.06 mmol)in DCM (1 mL) was added methyl carbonochloridate (4.72 mg, 0.05 mmol) inone portion at r.t. After 10 min, LC-MS indicated the completion ofreaction. The reaction was diluted with DCM, washed with saturatedaqueous NaHCO₃solution and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the desired product(3R,6R,7R,8E,23S)-6′-chloro-7-methoxy-11-methoxycarbonyl-13,13-(1,3-propylene)-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one(8 mg, 89.9% yield). LCMS: calc. for C₃₆H₄₅ClN₃O₇S [M+H]⁺:m/z=698.27/700.26; Found: 697.97/700.24. ¹H NMR (600 MHz, CDCl₃) δ 7.66(d, J=8.5 Hz, 1H), 7.43 (d, J=5.8 Hz, 1H), 7.29 (dd, J=8.3, 2.1 Hz, 1H),7.16 (dd, J=8.5, 2.4 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 6.90 (d, J=8.2 Hz,1H), 5.40-5.32 (m, 1H), 5.12 (app s, 1H), 4.18 (d, J=12.0 Hz, 1H), 4.04(d, J=11.9 Hz, 1H), 3.94-3.81 (m, 2H), 3.67 (app s, 6H), 3.58-3.49 (m,2H), 3.43-3.21 (m, 4H), 3.15 (m, 1H), 2.84-2.68 (m, 3H), 2.54-2.30 (m,3H), 2.12-1.77 (m, 9H), 1.63 (ddt, J=26.9, 18.3, 9.5 Hz, 2H), 1.47 (t,J=12.8 Hz, 1H). The sulfonamide NH was not observed due to solventexchange.

Example 68(3R,6R,7R,8E,23S)-6′-Chloro-7-methoxy-13,13-dimethyl-16,16-dioxo-spiro[21-oxa-16-thia-1,11,15-triazatetracyclo[15.7.2.03,6.020,25]hexacosa[8,17(26),18,20(25)]tetraene-23,1′-tetralin]-14-one

This compound was prepared using procedures analogous to those describedfor Example 26 using3-[(tert-butoxycarbonylamino)-2,2-dimethyl-propanoic acid to replace1-[(tert-butoxycarbonylamino)methyl]cyclobutanecarboxylic acid in Step2. LCMS: calc. for C₃₃H₄₃ClN₃O₅S [M+H]⁺: m/z=628.25/630.25; Found:628.0/630.2. ¹H NMR (300 MHz, CDCl₃) δ 8.07 (s, 1H), 7.72 (d, J=8.5 Hz,1H), 7.43 (dd, J=8.3, 1.7 Hz, 1H), 7.19 (dd, J=8.5, 2.1 Hz, 1H), 7.08(s, 2H), 6.94 (d, J=8.3 Hz, 1H), 5.99 (dt, J=15.6, 5.5 Hz, 1H), 5.64(dd, J=15.6, 7.7 Hz, 1H), 4.12-3.99 (m, 2H), 3.81-3.61 (m, 3H), 3.57 (t,J=7.3 Hz, 1H), 3.46 (dd, J=14.8, 4.5 Hz, 1H), 3.27 (s, 3H), 3.01 (dd,J=15.0, 10.3 Hz, 1H), 2.81 (dd, J=24.0, 11.2 Hz, 3H), 2.72-2.52 (m, 2H),2.32-2.15 (m, 1H), 1.90 (ddd, J=33.7, 25.8, 12.0 Hz, 5H), 1.77-1.54 (m,4H), 1.40 (t, J=12.1 Hz, 1H), 1.16 (s, 3H), 1.11 (s, 3H).

Example 69(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[[20]oxa[15]thia-1,14-diazatetracyclo[14.7.2.03,6.019,24-]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-oneand Example 70(3R,6R,7R,8Z,22S)-6′-chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and 1-but-3-enylcyclopropanecarboxylic acid in Step 3.The major product was assigned to Example 69(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one.LC-MS calc. for C₃₃H₄₀ClN₂O₅S [M+H]⁺: m/z=611.23/613.23; Found:611.0/612.8. Analytic HPLC: C18 column (4.6×150 mm, 100 Å); flow rate=1mL/min; mobile phase: 5% MeCN/H₂O (with 0.1% HCO₂H) 1 min, 5% to 95% 7min, 95% 5 min. λ=230 nm. t_(R)=4.6 min. ¹H NMR: (600 MHz, CDCl₃) δ 8.18(br s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.49 (dd, J=8.3, 2.1 Hz, 1H), 7.41(d, J=2.2 Hz, 1H), 7.18 (dd, J=8.5, 2.3 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H),7.00 (d, J=8.3 Hz, 1H), 5.30 (ddd, J=14.9, 9.9, 4.7 Hz, 1H), 5.08 (dd,J=15.2, 9.0 Hz, 1H), 4.18-4.07 (m, 2H), 3.68-3.56 (m, 2H), 3.32 (d,J=14.5 Hz, 1H), 3.15-3.11 (m, 1H), 3.09 (s, 3H), 2.97 (dd, J=8.8, 2.7Hz, 1H), 2.82-2.69 (m, 3H), 2.46-2.36 (m, 1H), 2.24-2.14 (m, 1H),2.09-1.98 (m, 2H), 1.93-1.53 (m, 9H), 1.43 (t, J=13.1 Hz, 1H), 1.39-1.19(m, 3H).

And the minor peak was assigned to Example 70(3R,6R,7R,8Z,22S)-6′-chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one.LC-MS calc. for C₃₃H₄₀ClN₂O₅S [M+H]⁺: m/z=611.23/613.23; Found:611.0/613.1. Analytic HPLC: C18 column (4.6×150 mm, 100 Å); flow rate=1mL/min; mobile phase: 5% MeCN/H₂O (with 0.1% HCO₂H) 1 min, 5% to 95% 7min, 95% 5 min. λ=230 nm. t_(R)=4.1 min (minor product). ¹H NMR: (600MHz, CDCl₃) δ 8.14 (br s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.47-7.45 (m,1H), 7.33 (d, J=2.2 Hz, 1H), 7.17 (dd, J=8.5, 2.3 Hz, 1H), 7.08 (d,J=2.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 5.40 (td, J=10.7, 3.9 Hz, 1H),5.07 (t, J=10.4 Hz, 1H), 4.15-4.05 (m, 2H), 3.74-3.58 (m, 3H), 3.40 (d,J=14.7 Hz, 1H), 3.28 (dd, J=14.8, 5.3 Hz, 1H), 3.15 (s, 3H), 2.77 (dddd,J=22.5, 16.6, 11.0, 4.9 Hz, 3H), 2.35 (t, J=7.5 Hz, 1H), 2.26-2.18 (m,1H), 2.10-1.75 (m, 8H), 1.68-1.52 (m, 3H), 1.48 (t, J=12.8 Hz, 1H), 1.34(dt, J=10.3, 5.7 Hz, 2H), 1.15 (ddd, J=9.7, 6.5, 4.3 Hz, 1H).

Example 71(3R,6R,7R,8E,11S,22S)-6′-Chloro-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

Step 1: (R,E)-3-(but-2-enoyl)-4-phenyloxazolidin-2-one

To a solution of (R)-(+)-4-Phenyl-1,3-oxazolidin-2-one (20.0 g, 122mmol) in THF (400 mL) was added n-BuLi (53.9 mL, 134 mmol) slowly at−78° C. The reaction solution was stirred at −78° C. for 20 min. Then(E)-but-2-enoyl chloride (14.09 g, 134 mmol) was added slowly. Thereaction solution was stirred at −78° C. for 0.5 h and then at 0° C. for15 mins. The reaction was quenched with saturated NH₄Cl solution (20mL), extracted with EA (200 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated to give crude mixture which waspurified by flash chromatography on a silica gel column with PE/EA=10/1to give (4R)-4-phenyl-3-[(E)-but-2-enoyl]oxazolidin-2-one (33 g, 58%yield). LC-MS calc. for C₁₃H₁₄NO3 [M+H]+m/z=232.09; Found: 232.0. ¹HNMR: (400 MHz, CDCl₃) δ 7.43-7.28 (m, 6H), 7.16-7.07 (m, 1H), 5.51 (dd,J=8.8, 4.0 Hz, 1H), 4.72 (t, J=8.8 Hz, 1H), 4.30 (dd, J=8.8, 4.0, Hz,1H), 1.96 (dd, J=6.8, 1.6 Hz, 3H).

Step 2: (4R)-4-phenyl-3-[(3S)-3-methylhex-5-enoyl]oxazolidin-2-one

To a solution of (4R)-4-phenyl-3-[(E)-but-2-enoyl]oxazolidin-2-one (11.5g, 49.73 mmol) in DCM (400 mL) was added TiCl₄ (28.3 g, 149.19 mmol) at−78° C. under N2. The solution was stirred at −78° C. for 20 min. Thenallyltrimethylsilane (17.0 g, 149 mmol) was added slowly at −78° C.After the addition the reaction solution was stirred at −78° C. for 4h., and quenched with saturated sodium bicarbonate solution. The organiclayer was separated, and the aqueous layer was extracted with EA (200mL×2). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with PE/EA=10/1 to give(4R)-4-phenyl-3-[(3S)-3-methylhex-5-enoyl]oxazolidin-2-one (5.33 g, 39%yield). The product was purified by recrystallization(n-pentane/Et₂O=60/1 with trace CH2C12 at 0° C.) to give(R)-3-((S)-3-methylhex-5-enoyl)-4-phenyloxazolidin-2-one (3 g withdr=97/3). LC-MS calc. for C₁₆H₂₀NO₃ [M+H]⁺ m/z=2734.14; Found: 274.0. ¹HNMR: (400 MHz, CDCl₃) δ 7.41-7.27 (m, 5H), 5.79-5.69 (m, 1H), 5.43 (dd,J=8.4, 3.6 Hz, 1H), 5.01-4.95 (m, 2H), 4.71-4.66 (m, 1H), 4.29-4.25 (m,1H), 3.03-2.68 (m, 2H), 2.15-1.91 (m, 3H), 0.92 (d, J=6.4 Hz, 3H).

Step 3: (S)-3-methylhex-5-enoic acid

To a solution of(4R)-4-phenyl-3-[(3S)-3-methylhex-5-enoyl]oxazolidin-2-one (1.6 g, 5.85mmol) in THF (25 mL) and water (5 mL) was added hydrogen peroxide (2.35mL, 23 mmol) and LiOH—H₂O (0.49 g, 11 mmol) at 0° C. Then the reactionsolution was stirred at 0° C. for 1 h. The reaction mixture wasconcentrated under reduced pressure. The residue was extracted with DCM.The aqueous solution was adjusted pH to 1 with HCl (2 N) and extractedwith DCM. The combined organic layers were dried over Na₂SO₄, filteredand concentrated to give (3S)-3-methylhex-5-enoic acid (600 mg, 80.0%yield). [α]²⁰ _(D)=−4.5 (c=0.79, CHCl₃) {lit. [α]²² _(D)=−2.8 (c=1.00,CHCl₃), Ref: Angew. Chem., 2009, 48, 8780-8783}. ¹H NMR: (400 MHz,CDCl₃) δ 5.74-5.83 (m, 1H), 5.04-5.08 (m, 2H), 2.40-2.44 (m, 1H),2.03-2.20 (m, 4H), 1.01 (d, J=6.4 Hz, 3H).

Step 4: (3R,6R,7R,8E,1S,22S)-6′-chloro-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 30 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (3S)-3-methylhex-5-enoic acid in Step 3. LC-MScalc. for C₃₂H₄₀ClN₂O₅S [M+H]⁺: m/z=599.2/601.2; Found 598.9/600.5. ¹HNMR (600 MHz, DMSO-d₆) 11.76 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.16 (dd,J=8.3, 2.1 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.94(d, J=8.3 Hz, 1H), 5.13-5.06 (m, 1H), 4.78 (dd, J=15.3, 9.0 Hz, 1H),4.93-3.96 (m, 2H), 3.43 (d, J=14.3 Hz, 2H), 3.01 (dd, J=15.0, 5.3 Hz,1H), 2.87 (s, 3H), 2.71-2.68 (m, 2H), 2.64-2.56 (m, 2H), 2.21-2.19 (m,1H), 2.05-1.87 (m, 5H), 1.76-1.64 (m, 4H), 1.54-1.44 (m, 3H), 1.38-1.31(m, 1H), 0.80 (d, J=6.3 Hz, 3H).

Example 72(3R,6R,7R,8E,12R,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

Step 1: hex-5-enoyl chloride

To the solution of hex-5-enoic acid (1.0 g, 8.76 mmol) in DCM (10 mL)was added oxalyl chloride (0.62 mL, 8.76 mmol) and DMF (0.10 mL) in oneportion. The reaction mixture was stirred at r.t. for 1 h., andconcentrated to give hex-5-enoyl chloride (1.16 g, 94.7% yield) whichwas directly used in next step reaction without further purification.

Step 2: (S)-4-benzyl-3-(hex-5-enoyl)oxazolidin-2-one

To a solution of (4R)-4-benzyloxazolidin-2-one (1.55 g, 8.75 mmol) inTHF (10 mL) was added LiCl (370 mg, 8.75 mmol) and triethylamine (2.65g, 26.25 mmol) slowly at 0° C. The reaction solution was stirred at 0°C. for 20 min. Then hex-5-enoyl chloride (1.16 g, 8.75 mmol) was addedslowly, and stirred at r.t. overnight. The reaction solution wasquenched with water (20 mL) and extracted with EA (40 mL). The organiclayer was washed with saturated NaHCO₃solution, dried over Na₂SO₄,filtered and concentrated to give crude mixture which was purified byflash chromatography on a silica gel column with PE/EA=10/1 to give(4R)-4-benzyl-3-hex-5-enoyl-oxazolidin-2-one (500 mg, 21% yield) as awhite oil. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.27 (m, 3H), 7.24-7.17 (m,2H), 5.83 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 5.13-4.95 (m, 2H), 4.68 (ddd,J=10.6, 6.9, 3.3 Hz, 1H), 4.27-4.07 (m, 2H), 3.30 (dd, J=13.4, 3.3 Hz,1H), 3.07-2.85 (m, 2H), 2.76 (dt, J=18.7, 9.3 Hz, 1H), 2.16 (q, J=7.3Hz, 2H), 1.89-1.74 (m, 2H).

Step 3: (R)-4-benzyl-3-((R)-2-methylhex-5-enoyl)oxazolidin-2-one

To a solution of (4R)-4-benzyl-3-hex-5-enoyl-oxazolidin-2-one (500.0 mg,1.83 mmol) in THF (5 mL) was added NaHMDS (2.5 mL, 1.0 M THF solution,2.5 mmol) slowly at −78° C. After stirring at −78° C. for 1 h.Iodomethane (778 mg, 5.49 mmol) was added slowly. The mixture wasstirred at −78° C. for additional 3 h. The mixture was quenched withCH3COOH (0.1 mL) and warmed up to r.t. Then water (15 mL) was added andextracted with EA (2×20 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting mixturewas purified by flash chromatography on a silica gel column withPE/EA=10/1 to give(4R)-4-benzyl-3-[(2R)-2-methylhex-5-enoyl]oxazolidin-2-one (200 mg, 38%yield) as a white oil. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.27 (m, 3H),7.23-7.20 (m, 2H), 5.84-5.74 (m, 1H), 4.70-4.64 (m, 1H), 4.22-4.13 (m,2H), 3.76-3.71 (m, 1H), 3.26 (dd, J=13.4, 3.3 Hz, 1H), 2.77 (dd, J=13.3,9.6 Hz, 1H), 2.12-2.06 (m, 2H), 1.93-1.84 (m, 1H), 1.55-1.48 (m, 1H),1.24 (d, J=6.9 Hz, 3H).

Step 4: (R)-2-methylhex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 41 using(4R)-4-benzyl-3-[(2R)-2-methylhex-5-enoyl]oxazolidin-2-one to replace(4R)-4-phenyl-3-[(3S)-3-methylhex-5-enoyl]oxazolidin-2-one in Step 3.[α]_(D) ²⁰−23.5 (c 0.79, CHCl₃) (lit. [α]_(D) ²³−25.0 (c 1.07, CHCl₃)).(Ref: Tetrahedron 2007 vol. 63 #26 p. 5754-5767). ¹H NMR (400 MHz,CDCl₃) δ 5.79 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.14-4.86 (m, 2H),2.58-2.44 (m, 1H), 2.16-2.02 (m, 2H), 1.89-1.71 (m, 1H), 1.53 (dt,J=13.9, 7.6 Hz, 1H), 1.25-1.12 (m, 3H). ¹³C NMR: (100 MHz, CDCl₃) δ183.2, 137.7, 115.2, 38.7, 32.5, 31.2, 16.8.

Step 5:(3R,6R,7R,8E,12R,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 30 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and using (R)-2-methylhex-5-enoic acid in Step 3. LC-MScalc. for C₃₂H₄₀ClN₂O₅S [M+H]⁺: m/z=599.2/601.2; Found: 599.0/600.9. ¹HNMR (600 MHz, DMSO-d₆) δ 11.82 (s, 1H), 7.69 (d, J=8.5 Hz, 1H),7.31-7.23 (m, 3H), 7.20 (d, J=2.4 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H),5.26-5.11 (m, 1H), 5.01-4.91 (m, 1H), 4.16 (d, J=12.3 Hz, 1H), 4.01 (d,J=12.3 Hz, 1H), 3.57-3.46 (m, 2H), 3.29 (d, J=14.3 Hz, 1H), 3.05-2.99(m, 1H), 2.98 (s, 3H), 2.83-2.78 (m, 1H), 2.74-2.68 (m, 1H), 2.22-2.17(m, 1H), 2.11-2.07 (m, 1H), 2.00 (dt, J=18.9, 6.8 Hz, 1H), 1.93 (d,J=14.0 Hz, 1H), 1.86-1.67 (m, 6H), 1.59-1.51 (m, 2H), 1.44 (td, J=14.9,6.6 Hz, 2H), 1.34 (dd, J=7.9, 4.4 Hz, 2H), 1.00 (d, J=6.5 Hz, 3H).

Example 73(3R,6R,7R,8E,23S)-6′-Chloro-7-methoxy-16,16-dioxo-spiro[21-oxa-16-thia-1,15-diazatetracyclo[15.7.2.03,6.020,25]hexacosa-8,17,19,25-tetraene-23,1′-tetralin]-14-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and hept-6-enoic acid in Step 3. LC-MS calc. forC₃₂H₄₀ClN₂O₅S [M+H]⁺: m/z=599.23/601.22; Found: 599.0/600.8. ¹H NMR (400MHz, DMSO-d₆) δ 11.96 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.29-7.24 (m,2H), 7.21 (d, J=2.4 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.3 Hz,1H), 5.60 (dt, J=15.6, 6.3 Hz, 1H), 5.09 (dd, J=15.6, 8.2 Hz, 1H), 4.21(d, J=12.1 Hz, 1H), 4.12 (d, J=12.1 Hz, 1H), 3.34-3.30 (m, 1H),3.27-3.18 (m, 2H), 3.08 (s, 3H), 2.81-2.66 (m, 3H), 2.41 (q, J=7.8 Hz,1H), 2.29-2.08 (m, 4H), 2.03-1.91 (m, 3H), 1.88-1.92 (m, 4H), 1.61-1.45(m, 4H), 1.45-1.37 (m, 1H), 1.25-1.20 (m, 3H), 1.15-1.06 (m, 1H).

Example 74(3R,6R,7R,8E,21S)-6′-Chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,13-diazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-one

This compound was prepared using procedures analogous to those describedfor Example 30 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and pent-4-enoic acid in Step 3. LC-MS calc. forC₃₀H₃₆ClN₂O₅S [M+H]⁺: m/z=571.20/573.19; Found: 570.9/572.7. ¹H NMR (600MHz, MeOH-d₄) δ 7.63 (d, J=8.3 Hz, 1H), 7.27-7.21 (m, 1H), 7.13 (d,J=2.2 Hz, 1H), 7.09-7.06 (m, 1H), 7.02 (d, J=2.5 Hz, 1H), 6.89 (d, J=8.3Hz, 1H), 5.05 (s, 1H), 4.91 (dd, J=15.6, 8.2 Hz, 1H), 4.33-4.28 (m, 1H),3.99-3.96 (m, 1H), 3.66-3.61 (m, 1H), 3.56-3.50 (m, 1H), 3.34-3.27 (m,3H), 3.02 (s, 3H), 2.78-2.71 (m, 4H), 2.31-2.28 (m, 2H), 2.15-2.02 (m,3H), 1.85-1.78 (m, 6H), 1.61 (dt, J=10.9, 9.0 Hz, 1H), 1.54-1.43 (m,3H).

Example 75(3R,6R,7S,8E,21S)-6′-Chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,13-diazatetracyclo[13.7.2.0˜3,6.0˜18,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and pent-4-enoic acid in Step 3. LC-MS calc. forC₃₀H₃₆ClN₂O₅S [M+H]⁺: m/z=571.20/573.19; Found: 570.9/572.8. ¹H NMR (600MHz, Methanol-d4) δ 7.49 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.3, 2.2 Hz,1H), 7.04 (ddd, J=12.3, 7.4, 2.3 Hz, 3H), 6.95 (d, J=8.3 Hz, 1H), 5.28(dd, J=15.6, 8.6 Hz, 1H), 4.54 (t, J=11.8 Hz, 1H), 4.15 (d, J=11.9 Hz,1H), 3.95 (d, J=11.9 Hz, 1H), 3.60 (dd, J=14.1, 3.3 Hz, 1H), 3.46 (d,J=14.2 Hz, 1H), 3.27 (dd, J=8.7, 2.5 Hz, 1H), 3.04 (s, 3H), 2.88 (dd,J=14.2, 11.1 Hz, 1H), 2.79-2.61 (m, 2H), 2.50 (qd, J=8.3, 4.0 Hz, 2H),2.41 (dt, J=14.7, 4.4 Hz, 1H), 2.34-2.22 (m, 1H), 2.19-2.03 (m, 3H),1.92-1.78 (m, 3H), 1.74-1.59 (m, 3H), 1.47 (dq, J=13.0, 9.9, 9.5 Hz,1H), 1.25-1.17 (m, 1H).

Example 76(3R,6R,7R,21S)-6′-Chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,13-diazatetracyclo[13.7.2.03,6.018,23]tetracosa-15,17,23-triene-21,1′-tetralin]-12-one

To a stirred solution of(3R,6R,7R,8E,21S)-6′-chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,13-diazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-one(Example 74, 7.9 mg, 0.01 mmol) was added platinum(IV) oxide anhydrous(0.63 mg). The reaction flask was charged with hydrogen and the reactionmixture was stirred at 20° C. with a hydrogen balloon. LC-MS showed fullconversion of starting material after 3 h. The solution was filteredthrough a pad of Celite and concentrated under reduced pressure Thecrude product was further purified by Prep-HPLC to afford(3R,6R,7R,21S)-6′-chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,13-diazatetracyclo[13.7.2.03,6.018,23]tetracosa-15,17,23-triene-21,1′-tetralin]-12-one(2.9 mg, 28.2% yield) as a white solid. LC-MS calc. for C₃₀H₃₈ClN₂O₅S[M+H]⁺: m/z=573.21/575.20; Found:572.8/574.6.

Example 77(3R,6R,7S,21S)-6′-Chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,13-diazatetracyclo[13.7.2.03,6.018,23]tetracosa-15,17,23-triene-21,1′-tetralin]-12-one

This compound was prepared using procedures analogous to those describedfor Example 46 using(3R,6R,7S,8E,21S)-6′-chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,13-diazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-one(Example 51). LC-MS calc. for C₃₀H₃₈ClN₂O₅S [M+H]⁺: m/z=573.21/575.20;Found:572.8/574.8.

Example 78(3R,6R,7R,8E,11S,12R,22S)-6′-Chloro-7-methoxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: (R)-3-((2R,3S)-2,3-dimethylhex-5-enoyl)-4-phenyloxazolidin-2-one

To a solution of LiHMDS, 1 M in THF (30.7 mL, 39.9 mmol) in THF (10 mL)was slowly added(R)-3-((S)-3-methylhex-5-enoyl)-4-phenyloxazolidin-2-one (5.46 g, 19.9mmol, Example 71, Step 2) in THF (1 mL) at −78° C. The mixture wasstirred at −78° C. for 1 h. Iodomethane (2.5 mL, 39 mmol) was addedslowly. The mixture was stirred at −78° C. for 3 h. Then the mixture wasstirred at −35° C. overnight. The mixture was quenched with saturatedNH₄Cl solution. The organic layer was separated, and the aqueous layerwas extracted with EA (3×20 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated to give crude solid. The crudesolid was purified by flash chromatography on a silica gel column withPE/EA=10/1 to give(R)-3-((2R,3S)-2,3-dimethylhex-5-enoyl)-4-phenyloxazolidin-2-one (1.4 g,24% yield) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ 7.40-7.27 (m,1H), 5.82-5.75 (m, 1H), 5.41 (dd, J=3.6 Hz, 8.8 Hz, 1H), 5.02 (t, J=6.8Hz, 2H), 4.66 (d, J=8.8 Hz, 1H), 4.24 (dd, J=3.6 Hz, 8.8 Hz, 1H),3.74-3.69 (m, 1H), 2.14-2.09 (m, 1H), 2.01-1.95 (m, 2H), 1.03 (d, J=6.8Hz, 3H), 0.88 (d, J=6.4 Hz, 3H). ¹³C NMR: (100 MHz, CDCl₃) δ 176.3,153.4, 139.4, 137.1, 129.2, 128.6, 125.7, 116.1, 69.7, 57.8, 41.9, 40.0,34.5, 15.5, 13.3.

Step 2: (2R,3S)-2,3-dimethylhex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 71 using(R)-3-((2R,3S)-2,3-dimethylhex-5-enoyl)-4-phenyloxazolidin-2-one toreplace (4R)-4-phenyl-3-[(3S)-3-methylhex-5-enoyl]oxazolidin-2-one inStep 3. dr=97:3. [α]²² _(D)=−33.8 (c=0.94, CHCl₃). ¹H NMR: (400 MHz,CDCl₃) δ 11.2 (br s, 1H), 5.82-5.73 (m, 1H), 5.06-5.01 (m, 2H),2.49-2.42 (m, 1H), 2.14-2.09 (m, 1H), 2.04-1.96 (m, 2H), 1.10 (d, J=6.8Hz, 3H), 0.90 (d, J=6.4 Hz, 3H).

Step 3:(3R,6R,7R,8E,11S,12R,22S)-6′-chloro-7-methoxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (2R,3S)-2,3-dimethylhex-5-enoic in Step 3. LC-MScalc. for C₃₃H₄₂ClN₂O₅S [M+H]⁺: m/z=613.25/615.25; Found: 612.9/615.0.¹H NMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.28(dd, J=8.5, 2.5 Hz, 1H), 7.27-7.18 (m, 2H), 7.16 (s, 1H), 7.03 (d, J=8.2Hz, 1H), 5.60-5.51 (m, 1H), 5.08-4.97 (m, 1H), 4.20 (d, J=12.1 Hz, 1H),4.04 (d, J=12.6 Hz, 1H), 3.27 (d, J=14.0 Hz, 2H), 3.03 (s, 3H),2.86-2.62 (m, 4H), 2.24-1.98 (m, 4H), 1.95-1.72 (m, 6H), 1.65-1.40 (m,5H), 1.24 (d, J=3.0 Hz, 3H), 0.84 (d, J=4.2 Hz, 3H).

Example 79(3R,6R,7S,8E,11S,12R,22S)-6′-Chloro-7-methoxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and (2R,3S)-2,3-dimethylhex-5-enoic acid (Example 47Step 2) in Step 3. LC-MS calc. for C₃₃H₄₂ClN₂O₅S [M+H]⁺:m/z=613.25/615.25; Found: 613.0/615.0. ¹H NMR (600 MHz, MeOH-d₄) δ 7.61(d, J=8.6 Hz, 1H), 7.46-7.41 (m, 2H), 7.19-7.14 (m, 2H), 7.05 (d, J=8.3Hz, 1H), 5.41-5.33 (m, 2H), 5.17 (s, 1H), 4.23 (d, J=11.8 Hz, 1H), 4.07(d, J=12.0 Hz, 1H), 3.60 (d, J=12.2 Hz, 1H), 3.53 (d, J=14.3 Hz, 2H),3.17 (s, 3H), 2.86-2.79 (m, 3H), 2.25-2.18 (m, 3H), 2.05 (d, J=7.0 Hz,3H), 1.94 (d, J=7.5 Hz, 2H), 1.80 (d, J=15.9 Hz, 2H), 1.63 (d, J=6.0 Hz,2H), 1.34-1.28 (m, 6H), 1.16 (d, J=6.9 Hz, 3H).

Example 80(3R,6R,7S,8E,22S)-6′-Chloro-7-methoxy-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and hex-5-enoic acid in Step 3. LC-MS calc. forC₃₁H₃₈ClN₂O₅S [M+H]⁺: m/z=585.21/587.21; Found: 585.0/586.9. ¹H NMR (600MHz, DMSO-d₆) 11.76 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.16 (dd, J=8.3,2.1 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.94 (d,J=8.3 Hz, 1H), 5.13-5.06 (m, 1H), 4.78 (dd, J=15.3, 9.0 Hz, 1H),4.93-3.96 (m, 2H), 3.43 (d, J=14.3 Hz, 2H), 3.01 (dd, J=15.0, 5.3 Hz,1H), 2.87 (s, 3H), 2.71-2.68 (m, 2H), 2.64-2.56 (m, 2H), 2.21-2.19 (m,1H), 2.05-1.87 (m, 5H), 1.76-1.64 (m, 4H), 1.54-1.44 (m, 3H), 1.38-1.31(m, 1H), 0.80 (d, J=6.3 Hz, 3H).

Example 81(3R,6R,7S,8E,12R,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 30 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and (R)-2-methylhex-5-enoic acid (Example 72, Step 4)in Step 3. LC-MS calc. for C₃₂H₄₀ClN₂O₅S [M+H]⁺: m/z=599.2/601.2; Found:599.4/601.5. ¹H NMR (600 MHz, MeOH-d₄) δ 7.58 (d, J=8.4 Hz, 1H), 7.51(d, J=2.3 Hz, 1H), 7.44 (dd, J=8.4, 2.2 Hz, 1H), 7.20-7.13 (m, 2H), 7.08(d, J=8.3 Hz, 1H), 5.12 (dd, J=15.4, 8.3 Hz, 1H), 4.99-4.89 (m, 1H),4.25 (d, J=12.0 Hz, 1H), 4.04 (d, J=11.9 Hz, 1H), 3.68 (dd, J=14.6, 4.3Hz, 1H), 3.53 (d, J=14.3 Hz, 1H), 3.29 (dd, J=8.9, 2.7 Hz, 1H), 3.13 (s,3H), 2.88-2.80 (m, 3H), 2.57 (tt, J=9.0, 4.5 Hz, 1H), 2.35 (ddd, J=10.5,6.7, 3.0 Hz, 1H), 2.21 (dt, J=9.6, 3.3 Hz, 1H), 2.09-1.98 (m, 2H),1.99-1.90 (m, 2H), 1.88-1.73 (m, 5H), 1.64-1.53 (m, 3H), 1.17 (d, J=7.0Hz, 3H).

Example 82(3R,6R,7S,8E,11S,22S)-6′-Chloro-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 30 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and (S)-3-methylhex-5-enoic acid (Example 71, Step 3)in Step 3. LC-MS calc. for C₃₂H₄₀ClN₂O₅S [M+H]⁺: m/z=599.2/601.2; Found:599.3/601.1 ¹H NMR (600 MHz, MeOH-d₄) δ 7.59 (d, J=8.4 Hz, 1H),7.48-7.41 (m, 2H), 7.18-7.14 (m, 2H), 7.08 (d, J=8.2 Hz, 1H), 5.17 (dd,J=15.4, 7.9 Hz, 1H), 5.09-5.02 (m, 1H), 4.27 (d, J=11.9 Hz, 1H), 4.03(d, J=11.9 Hz, 1H), 3.74-3.67 (m, 1H), 3.36 (d, J=10.2 Hz, 1H), 3.14 (s,3H), 3.06 (dd, J=14.1, 11.4 Hz, 1H), 2.87-2.74 (m, 3H), 2.63-2.58 (m,1H), 2.39 (dd, J=14.7, 2.6 Hz, 1H), 2.25-2.19 (m, 1H), 2.13-1.92 (m,7H), 1.87-1.67 (m, 5H), 1.62-1.57 (m, 2H), 1.01 (d, J=6.6 Hz, 3H).

Example 83(3R,6R,7S,8E,23S)-6′-Chloro-7-methoxy-16,16-dioxo-spiro[21-oxa-16-thia-1,15-diazatetracyclo[15.7.2.03,6.020,25]hexacosa-8,17,19,25-tetraene-23,1′-tetralin]-14-one

This compound was prepared using procedures analogous to those describedfor Example 30 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and hept-6-enoic acid in Step 3. LC-MS calc. forC₃₂H₄₀ClN₂O₅S [M+H]⁺: m/z=599.23/601.23; Found: 598.8/601.1. ¹H NMR (400MHz, DMSO-d₆) δ 12.00 (s, 1H), 7.59-7.54 (m, 1H), 7.36 (dd, J=8.4, 2.1Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 7.24-7.20 (m, 2H), 7.11 (d, J=8.3 Hz,1H), 5.13 (dd, J=15.6, 8.0 Hz, 1H), 4.85 (ddd, J=14.9, 8.2, 5.2 Hz, 1H),4.20 (d, J=11.9 Hz, 1H), 3.99 (d, J=12.0 Hz, 1H), 3.61 (dd, J=8.0, 3.5Hz, 1H), 3.55 (dd, J=14.0, 2.9 Hz, 1H), 3.34-3.24 (m, 2H), 3.10 (s, 3H),3.04-2.98 (m, 1H), 2.79-2.72 (m, 2H), 2.45 (dt, J=8.6, 4.4 Hz, 1H),2.40-2.33 (m, 1H), 2.26 (ddd, J=12.4, 8.0, 3.9 Hz, 1H), 2.11 (ddd,J=13.0, 6.3, 3.0 Hz, 1H), 2.06-1.98 (m, 1H), 1.94-1.91 (m, 1H),1.88-1.70 (m, 5H), 1.70-1.62 (m, 2H), 1.58-1.47 (m, 3H), 1.39 (td,J=9.1, 4.8 Hz, 1H), 1.17-1.10 (m, 1H).

Example 84(3R,6R,7S,8E,11R,22S)-6′-Chloro-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

Step 2: (R)-3-methylhex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 71 Step 1-3 using (S)-(+)-4-Phenyl-1,3-oxazolidin-2-one toreplace (R)-(+)-4-Phenyl-1,3-oxazolidin-2-one in Step 1. [α]²⁰ _(D)=+3.6(c=0.74, CHCl₃). ¹H NMR: (400 z, CDCl₃) 5.83-5.74 (m, 1H), 5.10-5.04 (m,2H), 2.44-2.40 (m, 1H), 2.23-2.03 (m, 4H), 1.01 (d, J=6.0 Hz, 3H).

Step 2: (3R,6R,7S,8E, 1R,22S)-6′-chloro-7-methoxy-11-methyl-1,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),179(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and (R)-3-methylhex-5-enoic acid in Step 3. LC-MS calc.for C₃₂H₄₀ClN₂O₅S [M+H]⁺: m/z=599.2/601.2; Found: 599.0/601.0. ¹H NMR(600 MHz, DMSO-d₆) δ 11.94 (s, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.27 (dd,J=8.3, 2.1 Hz, 1H), 7.23 (dd, J=8.4, 2.5 Hz, 1H), 7.21 (d, J=2.5 Hz,1H), 7.07 (d, J=8.3 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 5.14-5.06 (m, 2H),4.13 (d, J=12.1 Hz, 1H), 4.04 (d, J=12.1 Hz, 1H), 3.52 (dd, J=14.5, 6.4Hz, 2H), 3.43-3.37 (m, 1H), 3.22-3.13 (m, 1H), 3.07 (s, 3H), 2.80-2.71(m, 3H), 2.45-2.41 (m, 1H), 2.21 (dd, J=16.7, 7.8 Hz, 1H), 2.18-2.12 (m,2H), 2.02-1.94 (m, 4H), 1.89-1.82 (m, 3H), 1.78-1.71 (m, 2H), 1.66 (t,J=11.2 Hz, 1H), 1.55 (p, J=9.2 Hz, 1H), 0.89 (d, J=6.9 Hz, 3H).

Example 85(3R,6R,7S,8E,12S,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

Step 1: (2S)-2-methylhex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 72 Step 2-4 using(4S)-4-benzyl-3-hex-5-enoyl-oxazolidin-2-one to replace(4R)-4-benzyl-3-hex-5-enoyl-oxazolidin-2-one in Step 2. ¹H NMR (400 MHz,CDCl₃) 5.76-5.86 (m, 1H), 4.99-5.09 (m, 2H), 2.50-2.55 (m, 1H),2.11-2.16 (m, 2H), 1.79-1.88 (m, 1H), 1.51-1.59 (m, 1H), 1.22 (d, J=7.2Hz, 3H).

Step 2:(3R,6R,7S,8E,12S,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and (2S)-2-methylhex-5-enoic acid in Step 3. LC-MScalc. for C₃₂H₄₀ClN₂O₅S [M+H]⁺: m/z=599.2/601.2; Found: 598.9/600.9. ¹HNMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.31 (d,J=8.5 Hz, 1H), 7.27-7.19 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 7.00 (d, J=2.1Hz, 1H), 5.18-5.07 (m, 2H), 4.16 (d, J=12.1 Hz, 1H), 4.04 (d, J=12.0 Hz,1H), 3.54-3.43 (m, 3H), 3.07 (s, 3H), 2.82-2.74 (m, 2H), 2.01 (dd,J=14.4, 6.7 Hz, 2H), 1.93-1.79 (m, 5H), 1.73-1.65 (m, 4H), 1.54-1.45 (m,3H), 1.33-1.17 (m, 4H), 0.96 (d, J=6.8 Hz, 3H).

Example 86(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[[20]oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

Step 1: ethyl 1-but-3-enylcyclobutanecarboxylate

To a solution of diisopropylamine (4.86 g, 48. mmol) in THF (25 mL) wasadded n-butyllithium (18.3 mL, 45 mmol, 2.5 M in hexane) at −65° C.slowly. After addition, the reaction mixture was allowed to warm slowlyto −10° C. and then cooled back to −65° C. Ethyl cyclobutanecarboxylate(5.6 g, 43 mmol) was added dropwise. The resulting mixture was stirredat −65° C. for 1 h., and then 4-bromobut-1-ene (7.08 g, 52 mmol) inN-[bis(dimethylamino)phosphoryl]-N-methyl-methanamine (10 mL, 43 mmol)was added. The reaction was stirred at ambient temperature overnight.The mixture was quenched with water at 0° C., and extracted with MTBE(2×20 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified byflash chromatography on a silica gel column to afford ethyl1-but-3-enylcyclobutanecarboxylate (7.78 g, 97% yield).

Step 2: 1-(but-3-en-1-yl)cyclobutane-1-carboxylic acid

Ethyl 1-but-3-enylcyclobutanecarboxylate (240.0 mg, 1.32 mmol) inmethanol (2 mL) and water (2 mL) was treated with lithium hydroxidemonohydrate (226 mg, 5.2 mmol). The reaction was heated and stirred at50° C. over weekend. After cooling, the reaction was adjusted with 1 NHCl to pH about 2. The mixture was extracted with EA (2×10 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column to afford pure1-but-3-enylcyclobutanecarboxylic acid (128.7 mg, 63% yield). LC-MScalc. for C₈H₁₃O₂ [M−H]⁻: m/z=153.1; Found: 153.0.

Step 3:(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and 1-(but-3-en-1-yl)cyclobutane-1-carboxylic acid inStep 3. LC-MS calc. for C₃₄H₄₂ClN₂O₅S [M+H]⁺: m/z=625.24/627.24; Found:625.0/627.3. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=8.5 Hz, 1H), 7.58 (dd,J=8.4, 2.1 Hz, 1H), 7.35 (d, J=1.7 Hz, 1H), 7.18 (dd, J=8.5, 2.2 Hz,1H), 7.11 (d, J=2.1 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.27-5.15 (m, 1H),4.86 (dd, J=15.1, 9.1 Hz, 1H), 4.26 (d, J=11.7 Hz, 1H), 4.15 (d, J=11.9Hz, 1H), 3.58 (d, J=14.4 Hz, 2H), 3.31 (ddd, J=35.6, 22.1, 11.1 Hz, 3H),3.11 (d, J=13.4 Hz, 2H), 3.01 (d, J=6.7 Hz, 2H), 2.84-2.70 (m, 2H), 2.63(d, J=22.6 Hz, 1H), 2.51 (dt, J=16.4, 9.1 Hz, 2H), 2.41-2.29 (m, 2H),2.13-1.74 (m, 10H), 1.56 (ddd, J=27.7, 19.1, 11.5 Hz, 5H).

Example 87(3R,6R,7R,8E,11S,12S,22S)-6′-Chloro-7-methoxy-12-(methoxymethyl)-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1:(R)-3-((2S,3S)-2-(methoxymethyl)-3-methylhex-5-enoyl)-4-phenyloxazolidin-2-one

To a solution of LiHMDS, 1M in THF (179 mL, 179 mmol) was slowly added(4R)-4-phenyl-3-[(3S)-3-methylhex-5-enoyl]oxazolidin-2-one (27.3 g, 99mmol, Example 41, Step 2) in THF (30 mL) at −78° C. After stirring at−78° C. for 2 h., bromo(methoxy)methane (11 mL, 179 mmol) was slowlyadded. The reaction mixture was stirred at −78° C. for additional 3 h.,and then stirred at −30° C. overnight. The mixture was quenched withsaturated NH₄Cl aqueous solution. The organic layer was separated andthe aqueous layer was extracted with EA (50 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure The residue solid was purified by silica gel with PE/EA=10/1 togive(R)-3-((2S,3S)-2-(methoxymethyl)-3-methylhex-5-enoyl)-4-phenyloxazolidin-2-one(11.6 g, 36% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.27 (m, 5H),5.80-5.70 (m, 1H), 5.48 (dd, J=8.8, 4.1 Hz, 1H), 5.04-4.99 (m, 2H), 4.65(t, J=8.8 Hz, 1H), 4.22-4.15 (m, 2H), 3.60-3.50 (m, 2H), 3.16 (s, 3H),2.20-2.12 (m, 1H), 2.05-1.95 (m, 2H), 0.92 (d, J=8.4 Hz, 3H).

Step 2: (2S,3S)-2-(methoxymethyl)-3-methylhex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 71, Step 3 using(4R)-4-phenyl-3-[(2S,3S)-2-(methoxymethyl)-3-methyl-hex-5-enoyl]oxazolidin-2-one.¹H NMR (400 MHz, CDCl₃) 5.81-5.71 (m, 1H), 5.07-5.03 (m, 2H), 3.65 (t,J=9.2 Hz, 1H), 3.57-3.54 (m, 1H), 3.12 (s, 3H), 2.64-2.59 (m, 1H),2.22-2.18 (m, 1H), 2.18-1.97 (m, 1H), 2.06-1.95 (m, 2H), 0.95 (d, J=6.6Hz, 3H).

Step 3:(3R,6R,7R,8E,11S,12S,22S)-6′-Chloro-7-methoxy-12-(methoxymethyl)-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (2S,3S)-2-(methoxymethyl)-3-methylhex-5-enoic acidin Step 3. LC-MS calc. for C₃₄H₄₄ClN₂O₆S [M+H]⁺: m/z=643.25/645.25;Found: 642.9/645.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.66 (d,J=8.5 Hz, 1H), 7.28 (dd, J=8.5, 2.4 Hz, 1H), 7.22 (d, J=2.3 Hz, 2H),7.14 (s, 1H), 7.03 (d, J=8.2 Hz, 1H), 5.60-5.52 (m, 1H), 5.08-4.99 (m,1H), 4.19-4.12 (m, 4H), 3.45 (t, J=9.2 Hz, 2H), 3.33-3.25 (m, 2H),3.19-3.11 (m, 3H), 3.04 (s, 3H), 2.86-2.65 (m, 4H), 2.55 (s, 3H), 2.09(q, J=6.2, 5.2 Hz, 2H), 2.01 (q, J=6.8, 6.1 Hz, 1H), 1.88-1.80 (m, 5H),1.64-1.36 (m, 5H).

Example 88(3R,6R,7R,8E,11S,12S,22S)-6′-Chloro-7-hydroxy-12-(methoxymethyl)-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using (3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 4) and (2S,3S)-2-(methoxymethyl)-3-methylhex-5-enoic acidin Step 3. LC-MS calc. for C₃₃H₄₂ClN₂O₆S [M+H]⁺: m/z=629.2/631.2; Found:628.9/631.1. ¹H NMR (600 MHz, DMSO-d₆) δ 11.69 (s, 1H), 7.65 (d, J=8.5Hz, 2H), 7.32-7.19 (m, 4H), 7.15 (s, 1H), 7.00 (d, J=7.7 Hz, 1H), 5.52(s, 1H), 5.27 (s, 1H), 4.53 (d, J=3.4 Hz, 1H), 4.27-3.93 (m, 3H), 3.55(s, 2H), 3.43 (t, J=9.2 Hz, 2H), 3.34 (s, 12H), 3.21 (dd, J=32.9, 8.9Hz, 5H), 2.94 (d, J=11.3 Hz, 1H), 2.85-2.68 (m, 3H), 2.11-1.97 (m, 3H),1.90 (d, J=13.2 Hz, 2H), 1.79 (d, J=19.7 Hz, 5H), 1.66-1.36 (m, 5H),0.60 (s, 4H).

Example 89(3R,6R,7R,8E,11S,12R,22S)-6′-Chloro-7-methoxy-12-(2-methoxyethyl)-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: tert-butyl(3R,4S)-4-methyl-3-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)hept-6-enoate

To a mixture of(4R)-4-phenyl-3-[(3S)-3-methylhex-5-enoyl]oxazolidin-2-one (Example 71Step 2, 20.0 g, 73.2 mmol) in THF (150 mL) at −78° C. was added thesolution of NaHMDS (2 M in THF) (54.8 mL, 109 mmol) dropwise. Themixture was stirred at −78° C. for 3.5 h. Then t-butyl bromoacetate(21.4 g, 109 mmol) was added dropwise. The mixture was stirred at −78°C. for 30 min., and then allowed to warm to −40° C. and stirred at −40°C. for 1 h. The mixture was quenched with 50 mL of saturated NH₄Claqueous solution, extracted with ethyl acetate (3×200 mL). The organiclayer was dried and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column with PE/EA=10:1to gettert-butyl-(3R,4S)-4-methyl-3-[-(4R)-2-oxo-4-phenyl-oxazolidine-3-carbonyl]hept-6-enoate(8 g, 27.2% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.27(m, 5H), 5.89-5.70 (m, 1H), 5.45-5.35 (m, 1H), 5.09-4.96 (m, 2H),4.75-4.61 (m, 1H), 4.29-4.20 (m, 2H), 2.67 (dd, J=16.9, 11.7 Hz, 1H),2.30 (dd, J=16.9, 3.4 Hz, 1H), 2.18 (dd, J=15.5, 8.6 Hz, 1H), 2.08-1.93(m, 2H), 1.32-1.19 (m, 9H), 0.87 (dd, J=19.0, 6.6 Hz, 3H).

Step 2:(3R,4S)-4-methyl-3-((4R)-2-oxo-4-phenyloxazolidine-3-carbonyl)hept-6-enoicacid

To a mixture oftert-butyl-(3R,4S)-4-methyl-3-[(4R)-2-oxo-4-phenyl-oxazolidine-3-carbonyl]hept-6-enoate(9.6 g, 24.7 mmol) in 50 mL of DCM was added trifluoroacetic acid (73mL, 991 mmol). The mixture was stirred at r.t. for 12 h. LC-MS showedthe reaction was complete. The mixture was concentrated under reducedpressure. To the residue was added water (60 mL). The mixture wasadjusted to pH ˜ 7 with saturated NaHCO₃aqueous solution (100 mL), andextracted with ethyl acetate (100 mL). The organic layer was dried andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with PE/EA=2:1 to afford(3R,4S)-4-methyl-3-[(4R)-2-oxo-4-phenyl-oxazolidine-3-carbonyl]hept-6-enoicacid (6.6 g, 79% yield) as a pale yellow solid. LC-MS calc. forC₁₈H₂₂NO₅ [M+H]⁺: m/z=332.14; Found: 332.2. ¹H NMR (400 MHz, DMSO-d₆) δ12.17 (s, 1H), 7.26-7.36 (m, 5H), 5.74-5.84 (m, 1H), 5.49 (dd, J=2.8,8.4 Hz, 1H), 5.01-5.08 (m, 2H), 4.76 (t, J=8.4 Hz, 1H), 4.17 (dt, J=3.2,11.6 Hz, 1H), 4.10 (dd, J=2.8, 8.8 Hz, 1H), 2.54 (dd, J=12.0, 17.2 Hz,1H), 2.34 (dd, J=3.2, 17.2 Hz, 1H), 1.99-2.13 (m, 3H), 0.76 (d, J=6.4Hz, 3H).

Step 3:(4R)-4-phenyl-3-[(2R,3S)-2-(2-hydroxyethyl)-3-methyl-hex-5-enoyl]oxazolidin-2-one

To a mixture of(3R,4S)-4-methyl-3-[(4R)-2-oxo-4-phenyl-oxazolidine-3-carbonyl]hept-6-enoicacid (3.0 g, 9.05 mmol) and triethylamine (3.7 g, 36 mmol) in 100 mL ofdry THF at −40° C. was added isobutyl chloroformate (2.47 g, 18.11mmol). The mixture was stirred at −40° C. for 1 h. Then sodiumborohydride (1.37 g, 36.21 mmol) in 30 mL of water was added. Themixture was stirred at −40° C. for 2 h. The reaction mixture was treatedwith 3 N HCl (80 mL) and allowed to warm to r.t. The organic solvent wasremoved under reduced pressure, and the aqueous solution was extractedwith DCM (100 mL). The organic layer was dried and concentrated toafford the crude product(4R)-4-phenyl-3-[(2R,3S)-2-(2-hydroxyethyl)-3-methyl-hex-5-enoyl]oxazolidin-2-one(5.6 g) which was directly used in next step reaction without furtherpurification. LC-MS calc. for C₁₈H₂₄NO₄ [M+H]⁺: m/z=318.16; Found:318.2.

Step 4:(4R)-4-phenyl-3-[(2R,3S)-2-(2-methoxyethyl)-3-methyl-hex-5-enoyl]oxazolidin-2-one

To a mixture of(4R)-4-phenyl-3-[(2R,3S)-2-(2-hydroxyethyl)-3-methyl-hex-5-enoyl]oxazolidin-2-one(600 mg, 1.89 mmol) in 20 mL of dry DCM was added trimethyloxoniumtetrafluoroborate (279 mg, 1.89 mmol) and proton sponge(1,8-bis(dimethylamino)naphthalene) (405 mg, 1.89 mmol). The mixture wasstirred at r.t. for 2 d. The mixture was concentrated under reducedpressure and the residue was dissolved in ethyl acetate (50 mL). Themixture was washed with 3 M HCl (30 mL). The organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure Theresidue was purified by flash chromatography on a silica gel column withPE/EA=10:1 to afford(4R)-4-phenyl-3-[(2R,3S)-2-(2-methoxyethyl)-3-methyl-hex-5-enoyl]oxazolidin-2-one(320 mg, 50% yield) as a colorless oil. LC-MS calc. for C₁₉H₂₆NO₄[M+H]⁺: m/z=332.18; Found: 332.2.

Step 5: (2R,3S)-2-(2-methoxyethyl)-3-methylhex-5-enoic acid(HHC001-80-1)

To a mixture of(4R)-4-phenyl-3-[(2R,3S)-2-(2-methoxyethyl)-3-methyl-hex-5-enoyl]oxazolidin-2-one(320 mg, 0.97 mmol) in 15 mL of THF and 3 mL of water at 0° C. was addedhydrogen peroxide (30% in water) (0.39 mL, 3.8 mmol) and lithiumhydroxide (46 mg, 1.9 mmol). The mixture was stirred at 0° C. for 1 hand then allowed to warm to r.t. and stirred at r.t. for 12 h. Theorganic solvent was removed and the aqueous solution was added 10 mL ofwater, adjusted to pH 3.0 with con. HCl, extracted with ethyl acetate(30 mL). The organic layer was dried and concentrated to get(2R,3S)-2-(2-methoxyethyl)-3-methyl-hex-5-enoic acid (90 mg, 47% yield)as a colorless oil. LC-MS calc. for C₁₀H₁₉O₃ [M+H]⁺: m/z=187.13; Found:169.2 ([M−H₂O+H]+). ¹H NMR (400 MHz, CDCl₃) δ 0.94 (d, J=6.4 Hz, 3H),1.71-1.79 (m, 1H), 1.85-1.92 (m, 1H), 1.93-2.01 (m, 2H), 2.13-2.21 (m,1H), 2.44-2.49 (m, 1H), 3.33 (s, 3H), 3.37-3.47 (m, 2H), 5.02 (s, 1H),5.05-5.06 (m, 1H), 5.71-5.82 (m, 1H).

Step 6:(3R,6R,7R,8E,11S,12R,22S)-6′-chloro-7-methoxy-12-(2-methoxyethyl)-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (2R,3S)-2-(2-methoxyethyl)-3-methyl-hex-5-enoicacid in Step 3. LC-MS calc. for C₃₅H₄₆ClN₂O₆S [M+H]⁺: m/z=657.28/659.28;Found: 657.1/658.8.

Example 90(3R,6R,7R,8E,11S,12R,22S)-6′-Chloro-12-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: (2R,3S)-2-(2-(tert-butoxy)-2-oxoethyl)-3-methylhex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 71 Step 3 using tert-butyl(3R,4S)-4-methyl-3-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)hept-6-enoate(Example 89 Step 1). ¹H NMR (400 MHz, CDCl₃) δ 0.91 (d, J=6.4 Hz, 3H),1.44 (s, 9H), 1.94-2.08 (m, 2H), 2.10-2.16 (m, 1H), 2.31 (dd, J=4.0 Hz,16.8 Hz, 1H), 2.61 (m, J=11.2 Hz, 16.8 Hz, 1H), 2.88 (m, J=4.0 Hz, 11.2Hz, 1H), 5.02-5.03 (m, 1H), 5.06 (m, J=1.2 Hz, 1H), 5.71-5.81 (m, 1H).

Step 2: tert-butyl 2-[(3R,6R,7R,8E,11S,12R,22S)-6′-chloro-7-methoxy-11-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,14diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-12-yl]acetate

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and(2R,3S)-2-(2-(tert-butoxy)-2-oxoethyl)-3-methylhex-5-enoic acid in Step3. LC-MS calc. for C₃₈H₅₀ClN₂O₇S [M+H]⁺: m/z=713.3/715.3; Found:712.9/715.2.

Step 3:2-[(3R,6R,7R,8E,11S,12R,22S)-6′-chloro-7-methoxy-11-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-12-yl]aceticacid

A solution of tert-butyl2-[(3R,6R,7R,8E,11S,12R,22S)-6′-chloro-7-methoxy-11-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-12-yl]acetate(25.0 mg, 0.04 mmol) in CH2Cl2 (1 mL) at 0° C. was treated with2,2,2-trifluoroacetic acid (TFA) (0.5 mL) drop-wise. The reaction wasstirred at r.t. overnight. The volatile components are removed undervacuum to afford the crude product2-[(3R,6R,7R,8E,11S,12R,22S)-6′-chloro-7-methoxy-11-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-12-yl]aceticacid (21 mg) which was directly used in next step without furtherpurification. LC-MS: calc. for C₃₄H₄₂ClN₂O₇S [M+H]⁺: m/z=657.2/659.2;Found: 657.0/659.3.

Step 4: (3R,6R,7R,8E,11S,12R,22S)-6′-chloro-12-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

A mixture of2-[(3R,6R,7R,8E,11S,12R,22S)-6′-chloro-7-methoxy-11-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-12-yl]aceticacid (20.0 mg, 0.03 mmol), 3,3-difluoroazetidine hydrochloride (7.94 mg,0.06 mmol), and HATU (34.71 mg, 0.09 mmol) in DCM (1 mL) was stirred at0° C. for 1 h., and then diisopropylethylamine (11.78 mg, 0.09 mmol) wasadded. The mixture was stirred at r.t. overnight. LC-MS analysisindicated complete conversion. The reaction was quenched with 0.5M HCl(1.0 mL) and volatile components were removed under reduced pressure.The residue was purified by prep-HPLC on a C18 column with ACN and waterto afforded(3R,6R,7R,8E,11S,12R,22S)-6′-chloro-12-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(2 mg, 9.0% yield). LC-MS calc. for C₃₇H₄₅ClF₂N₃O₆S [M+H]⁺:m/z=732.2/734.2; Found: 732.0/734.3.

Example 912-[(3R,6R,7R,8E,11S,12R,22S)-6′-Chloro-7-methoxy-11-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-12-yl]-N,N-dimethyl-acetamide

This compound was prepared using procedures analogous to those describedfor Example 149 Step 4 using dimethylamine HCl salt. LC-MS: calc. forC₃₆H₄₇ClN₃O₆S [M+H]=684.2/686.2; Found: 684.0/686.3.

Example 92(3R,6R,7R,8E,11S,12R,22S)-6′-Chloro-7-methoxy-11-methyl-12-(2-morpholino-2-oxo-ethyl)-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 149 Step 4 using morpholine. LC-MS: calc. for C₃₈H₄₉ClN₃O₇S[M+H]=726.3/728.3; Found: 726.7/728.1.

Example 93(3R,6R,7R,8E,11S,12S,22S)-6′-chloro-7-methoxy-12-(2-methoxyethoxymethyl)-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: (2S,3S)-2-(2-methoxyethoxymethyl)-3-methyl-hex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 88 Step 1-2 using(4R)-4-phenyl-3-[(3S)-3-methylhex-5-enoyl]oxazolidin-2-one (Example 86Step 2) and 1-(chloromethoxy)-2-methoxy-ethane in Step 1. ¹H NMR (400MHz, CDCl₃) δ 5.81-5.72 (m, 1H), 5.06-5.03 (m, 2H), 3.74 (t, J=9.2 Hz1H), 3.67-3.60 (m, 3H), 3.56-3.52 (m, 2H), 3.38 (s, 3H), 2.67-2.65 (m,1H), 2.21-2.19 (m, 1H), 2.03-1.96 (m, 2H), 0.96 (d, J=6.4 Hz, 3H).

Step 2:(3R,6R,7R,8E,11S,12S,22S)-6′-chloro-7-methoxy-12-(2-methoxyethoxymethyl)-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and(2S,3S)-2-(2-methoxyethoxymethyl)-3-methyl-hex-5-enoic acid in Step 3.LC-MS calc. for C₃₆H₄₇ClN₂O₇S [M+H]⁺: m/z=687.28/689.28; Found:

Example 94(3R,6R,7R,8E,11S,12S,22S)-6′-Chloro-12-(hydroxymethyl)-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: (2S,3S)-3-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)hex-5-enoicacid

This compound was prepared using procedures analogous to those describedfor Example 88 Step 1-2 using(4R)-4-phenyl-3-[(3S)-3-methylhex-5-enoyl]oxazolidin-2-one (Example 86Step 2) and (2-(chloromethoxy)ethyl)trimethylsilane in Step 1. ¹H NMR(400 MHz, CDCl₃) δ 5.78-5.71 (m, 1H), 5.06-5.02 (m, 2H), 3.66-3.51 (m,4H), 2.60-2.57 (m, 1H), 2.30-2.11 (m, 1H), 2.03-1.96 (m, 2H), 1.01-0.85(m, 5H), 0.01 (s, 9H).

Step 2: (3R,6R,7R,8E,11S,12S,22S)-6′-chloro-7-methoxy-11-methyl-15,15-dioxo-12-(2-trimethylsilylethoxymethyl)spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and(2S,3S)-3-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)hex-5-enoic acid inStep 3. LC-MS calc. for C₃₈H₅₄ClN₂O₆SiS [M+H]⁺: m/z=729.31; Found:729.7.

Step 3:(3R,6R,7R,8E,11S,12S,22S)-6′-chloro-12-(hydroxymethyl)-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

To a solution of(3R,6R,7R,8E,11S,12S,22S)-6′-chloro-7-methoxy-11-methyl-15,15-dioxo-12-(2-trimethylsilylethoxymethyl)spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(10 mg) in DCM (1 mL) was added 50% TFA (1 mL). The resulting mixturewas stirred at r.t. for 2 h. The mixture was concentrated under reducedpressure. The residue was purified on C18 column with MeCN/H₂O (30-100%)to afford the desired product (5 mg). LC-MS calc. for C₃₃H₄₂ClN₂O₆S[M+H]⁺: m/z=629.24; Found: 629.0.

Example 95(3R,6R,7R,8E,12S,22S)-6′-Chloro-12-(hydroxymethyl)-7-methoxy-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: (4R)-3-hex-5-enoyl-4-phenyl-oxazolidin-2-one

To a solution of (R)-(−)-phenyl-2-oxazolidinone (15.0 g, 93 mmol) in THF(500 mL) was added n-BuLi (80.9 mL, 202 mmol) slowly at −78° C. Thereaction solution was stirred at −78° C. for 20 min. Then hex-5-enoylchloride (26.8 g, 202 mmol) was added slowly. The reaction was stirredat −78° C. for 0.5 h and allowed to warm to ambient temperatureovernight. The reaction was quenched with saturated NH₄Cl solution (100mL), and extracted with EA (100 mL×2). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to give crudemixture which was purified by flash chromatography on a silica gelcolumn with PE/EA (10/1) to give(4R)-3-hex-5-enoyl-4-phenyl-oxazolidin-2-one (15 g, 31% yield). ¹H NMR:(400 MHz, CDCl₃) 7.29-7.43 (m, 5H), 5.73-5.83 (m, 1H), 5.43-5.46 (m,1H), 4.96-5.04 (m, 2H), 4.71 (t, J=8.8 Hz, 1H), 4.28-4.31 (m, 1H),2.95-2.99 (m, 2H), 2.06-2.12 (m, 2H), 1.70-1.77 (m, 2H).

Step 2: (S)-2-((2-(trimethylsilyl)ethoxy)methyl)hex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 88 Step 1-2 using(4R)-3-hex-5-enoyl-4-phenyl-oxazolidin-2-one and(2-(chloromethoxy)ethyl)trimethylsilane in Step 1. ¹H NMR (400 MHz,CDCl₃) δ 5.78 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.09-4.88 (m, 2H),3.58-3.39 (m, 4H), 2.67 (ddd, J=15.5, 7.8, 5.6 Hz, 1H), 2.23-2.07 (m,2H), 1.81 (ddd, J=21.5, 11.5, 5.8 Hz, 1H), 1.68-1.52 (m, 1H), 0.99-0.81(m, 2H), 0.04-−0.01 (m, 9H).

Step 3:(3R,6R,7R,8E,12S,22S)-6′-chloro-12-(hydroxymethyl)-7-methoxy-1S,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 94 Step 2-3 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (S)-2-((2-(trimethylsilyl)ethoxy)methyl)hex-5-enoicacid. LC-MS calc. for C₃₂H₄₀ClN₂O₆S [M+H]⁺: m/z=615.22; Found: 615.0.

Example 96(3R,6R,7R,8E,12S,22S)-6′-Chloro-12-(methoxymethyl)-7-methoxy-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: (S)-2-(methoxymethyl)hex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 88 Step 1-2 using(4R)-3-hex-5-enoyl-4-phenyl-oxazolidin-2-one and bromo(methoxy)methanein Step 1. ¹H NMR (400 MHz, CDCl₃) δ 5.84-5.74 (m, 1H), 5.08-4.98 (m,2H), 3.59 (dd, J=9.2, 8.0 Hz, 1H), 3.52 (dd, J=9.2, 5.2 Hz, 1H), 3.37(s, 3H), 2.74-2.67 (m, 2H), 2.17-2.10 (m, 2H), 1.85-1.74 (m, 1H),1.66-1.57 (m, 1H).

Step 2:(3R,6R,7R,8E,12S,22S)-6′-chloro-12-(methoxymethyl)-7-methoxy-1S,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (S)-2-(methoxymethyl)hex-5-enoic acid in Step 3.LC-MS calc. for C₃₃H₄₂ClN₂O₆S [M+H]⁺: m/z=629.24/631.24; Found:

Example 97(3R,6R,7R,8E,12S,22S)-6′-Chloro-12-((2-methoxyethoxy)methyl)-7-methoxy-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: (S)-2-((2-methoxyethoxy)methyl)hex-5-enoic acid

This compound was prepared using procedures analogous to those describedfor Example 88 Step 1-2 using(4R)-3-hex-5-enoyl-4-phenyl-oxazolidin-2-one and1-(chloromethoxy)-2-methoxyethane in Step 1. ¹H NMR (400 MHz, CDCl₃) δ5.85-5.75 (m, 1H), 5.09-4.98 (m, 2H), 3.72-3.69 (m, 1H), 3.67-3.60 (m,3H), 3.56-3.52 (m, 2H), 3.36 (s, 3H), 2.78-2.71 (m, 1H), 2.19-2.09 (m,2H), 1.81-1.71 (m, 1H), 1.69-1.59 (m, 1H).

Step 2:(3R,6R,7R,8E,12S,22S)-6′-chloro-12-((2-methoxyethoxy)methyl)-7-methoxy-15,15-dioxo-spiro[20-oxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (S)-2-((2-methoxyethoxy)methyl)hex-5-enoic acid inStep 3. LC-MS calc. for C₃₅H₄₆ClN₂O₇S [M+H]⁺: m/z=673.26/675.26; Found:

Example 98(3R,6R,24S)-6′-Chloro-8,8,17,17-tetraoxo-spiro[22-oxa-8,17-dithia-1,16-diazapentacyclo[16.7.2.19,13.03,6.021,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one

To a solution of(3R,6R,24S)-6′-chloro-17,17-dioxo-spiro[22-oxa-8,17-dithia-1,16-diazapentacyclo[16.7.2.19,13.03,6.021,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one(3.5 mg, Example 25) in DCM (0.50 mL) was added m-CPBA (77 wt %) (2.0mg, 0.01 mmol) under N2, and stirred at r.t. for 18 h. The reactionmixture was concentrated under reduced pressure. The residue (whitesolid) was purified by FCC (15.5 g C18, 20→100% MeCN in H₂O, wet-loadedin DMSO). Fractions containing pure product were combined andconcentrated under reduced pressure to afford(3R,6R,24S)-6′-chloro-8,8,17,17-tetraoxo-spiro[22-oxa-8,17-dithia-1,16-diazapentacyclo[16.7.2.19,13.03,6.021,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one(1.66 mg) as a white solid. LCMS m/z calc. for C₃₂H₃₄ClN₂O₆S₂ [M+H]⁺:m/z=641.15/643.15; Found: 641.1/643.1.

Example 99(3R,6R,10E,23S)-6′-Chloro-16,16-dioxo-spiro[8,21-dioxa-16-thia-1,15-diazatetracyclo[15.7.2.03,6.020,25]hexacosa-10,17(26),18,20(25)-tetraene-23,1′-tetralin]-14-one

Step 1:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(allyloxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

A solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(56.8 mg, 0.08 mmol, Example 18 Step 2) in DMF (0.5 mL) was charged withsodium hydride (60% dispersion in mineral oil, 14 mg, 0.36 mmol)(caution: evolves H2) at r.t. and was purged with N₂. After 1 min., themixture was charged with allyl bromide (27 uL, 0.32 mmol) and stirred atr.t. for 22 h. The reaction mixture was quenched with water (1 mL)(caution: evolves H2), diluted with sat. NH₄Cl (20 mL) and extractedwith EtOAc (30 mL). The organic layer was separated, washed with water(2×20 mL) and brine (2×20 mL). The organic layer was dried over Na₂SO₄,filtered, concentrated under reduced pressure to yield(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(allyloxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(67 mg) without further purification.

Step 2:(3S)-6′-chloro-5-[[(1R,2R)-2-(allyloxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

The crude(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(allyloxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(67 mg) was dissolved in DCM (800 μL). The flask was purged with N₂,then charged with TFA (800 μL), and stirred at r.t. for 22 h. Thereaction mixture was co-evaporated with DCM twice under reducedpressure, and diluted with EtOAc (30 mL), washed with sat. NaHCO₃(20mL), water (20 mL), and brine (20 mL). The organic layer was dried overNa₂SO₄, filtered, concentrated under reduced pressure to yield(3S)-6′-chloro-5-[[(1R,2R)-2-(allyloxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(62.1 mg) as a yellow/white solid. LCMS m/z calc. for C₂₇H₃₄ClN₂O₄S[M+H]⁺: m/z=517.19/519.19; Found: 517.1/519.2.

Step 3:N-[(3S)-6′-chloro-5-[[(1R,2R)-2-(allyloxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylpent-4-enamide

A mixture of(3S)-6′-chloro-5-[[(1R,2R)-2-(allyloxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(40.95 mg, 0.08 mmol), 4-(dimethylamino)pyridine (DMAP) (48.38 mg, 0.40mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDCI) (53.14 mg, 0.28 mmol) under N₂ was dissolved in DCM (1 mL). Tothe solution was added 4-pentenoic acid (24 uL, 0.24 mmol). The mixturewas stirred at r.t. for 2.5 h. The reaction mixture was diluted withEtOAc (30 mL), washed twice with brine (20 mL) and 0.1 N HCl (5 mL), andwashed with brine (20 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated under reduced pressure to yieldN-[(3S)-6′-chloro-5-[[(1R,2R)-2-(allyloxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylpent-4-enamide(36 mg, 76% yield) as a clear yellow glass (36 mg). R_(f)=0.44 (2:1hexanes:EtOAc); LCMS m/z calc. for C₃₂H₄₀ClN₂O₅S [M+H]⁺:m/z=599.23/601.23; Found: 599.3/601.2.

Step 4:(3R,6R,10E,23S)-6′-chloro-16,16-dioxo-spiro[8,21-dioxa-16-thia-1,15-diazatetracyclo[15.7.2.03,6.020,25]hexacosa-10,17(26),18,20(25)-tetraene-23,1′-tetralin]-14-one

A solution ofN-[(3S)-6′-chloro-5-[[(1R,2R)-2-(allyloxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylpent-4-enamide(28.0 mg, 0.05 mmol) in DCM (2 mL) was purged with N₂ and was chargedwith a solution of(1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI)chloride (Hoveyda-Grubbs II) (2.9 mg) in DCM (1 mL). The reactionmixture was stirred at r.t. for 1 d. The reaction mixture was chargedwith 3 drops DMSO, concentrated under reduced pressure, and purified byFCC (15.5 g C18, 40→100% MeCN in H₂O, wet-loaded in DMSO). Fractionscontaining pure product were combined and concentrated under reducedpressure and heat (−50° C.) to yield the desired(3R,6R,10E,23S)-6′-chloro-16,16-dioxo-spiro[8,21-dioxa-16-thia-1,15-diazatetracyclo[15.7.2.03,6.020,25]hexacosa-10,17(26),18,20(25)-tetraene-23,1′-tetralin]-14-one(14.4 mg, 51% yield) as a white solid. LCMS m/z calc. for C₃₀H₃₅ClN₂O₅S[M+H]⁺: m/z=571.20/573.20; Found: 571.1/573.0; ¹H NMR (500 MHz, MeCN-d₃)δ 9.31 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.36 (dd, J=2.2, 8.4 Hz, 1H),7.20 (d, J=2.2 Hz, 1H), 7.19-7.13 (m, 2H), 6.98 (d, J=8.4 Hz, 1H),5.48-5.38 (m, 1H), 4.95 (dt, J=5.5, 15.8 Hz, 1H), 4.35 (d, J=11.9 Hz,1H), 4.02 (d, J=11.9 Hz, 1H), 3.64 (dd, J=5.9, 13.0 Hz, 1H), 3.59 (dd,J=4.6, 14.4 Hz, 1H), 3.54 (dt, J=1.5, 5.0, 12.7 Hz, 1H), 3.50 (d, J=14.6Hz, 1H), 3.35 (d, J=14.4 Hz, 1H), 3.29 (dd, J=6.3, 9.8 Hz, 1H), 3.19(dd, J=4.1, 9.8 Hz, 1H), 3.08 (dd, J=10.5, 14.5 Hz, 1H), 2.85 (td,J=4.3, 9.4 Hz, 1H), 2.77 (q, J=6.6, 7.8 Hz, 2H), 2.46-2.40 (m, 1H),2.40-2.34 (m, 1H), 2.27-2.18 (m, 3H), 2.08-2.04 (m, 1H), 2.01-1.96 (m,1H), 1.88-1.82 (m, 3H), 1.71-1.52 (m, 3H).

Example 100(3R,6R,7S,8E,15S,24S)-6′-Chloro-7-methoxy-17,17-dioxo-spiro[22-oxa-17-thia-1,11-diazapentacyclo[16.7.2.03,6.011,15.021,26]heptacosa-8,18,20,26-tetraene-24,1′-tetralin]-16-one

Step 1: methyl allyl-L-prolinate

To a solution of L-proline methyl ester hydrochloride (6.64 g, 40.0mmol) in DMF (80 mL) was added Et3N (223 mL, 160 mmol) and Allyl bromide(9.7 g, 80 mmol) at 0° C. The mixture was stirred at ambient temperaturefor 12 h. The reaction mixture was poured into water, and extracted withethyl acetate (3×30 mL). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, and evaporated under reducedpressure. The residue was purified by flash chromatography on a silicagel column (EtOAc/hexane=1:3) to give methyl(2S)-1-allylpyrrolidine-2-carboxylate (5.4 g, 79% yield) as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ 6.04-5.94 (m, 1H), 5.20 (dd, J=16.8,1.6 Hz, 1H), 5.16 (d, J=10.0 Hz, 1H), 3.71 (s, 3H), 3.33-3.28 (m, 1H),3.16-3.11 (m, 3H), 2.39-2.37 (m, 1H), 2.17-2.04 (m, 1H), 1.95-1.90 (m,2H), 1.82-1.79 (m, 1H).

Step 2: (2S)-1-allylpyrrolidine-2-carboxylic acid HCl salt

To a solution of methyl (2S)-1-allylpyrrolidine-2-carboxylate (2.0 g, 11mmol) in THF (10 mL) and water (5 mL) was added NaOH (945 mg, 23 mmol).After stirring for 18 h at rt., the reaction mixture was added water (10mL) and washed with ethyl acetate (2×20 mL). The aqueous layer wasacidified with 1 N HCl (10 mL) and washed with ethyl acetate (10 mL).The aqueous layer was concentrated under reduced pressure. The residuewas dissolved in DCM/MeOH (1:1, 20 mL). The salt was removed byfiltration and the filtrate was evaporated under reduced pressure toafford (2S)-1-allylpyrrolidine-2-carboxylic acid HCl salt (1.9 g, 84%yield) as a white solid. [a]_(D) ²⁰=−74.0 (c=1.0, MeOH). ¹H NMR (400MHz, MeOH-d₄) δ 5.98-5.94 (m, 1H), 5.60 (dd, J=17.2, 1.2 Hz, 1H), 5.51(d, J=10.0 Hz, 1H), 4.09-4.05 (m, 1H), 3.95-3.90 (m, 1H), 3.86-3.81 (m,1H), 3.74-3.68 (m, 1H), 3.23-3.18 (m, 1H), 2.54-2.48 (m, 1H), 2.20-2.11(m, 2H), 2.03-1.96 (m, 1H).

Step 3:(3R,6R,7S,8E,15S,24S)-6′-Chloro-7-methoxy-17,17-dioxo-spiro[22-oxa-17-thia-1,11-diazapentacyclo[16.7.2.03,6.011,15.021,26]heptacosa-8,18,20,26-tetraene-24,1′-tetralin]-16-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and allylpyrrolidine-2-carboxylic acid in Step 3. LC-MScalc. for C₃₃H₄₁ClN₃O₅S [M+H]⁺: m/z=626.24/628.24; Found: 626.0/628.0.¹H NMR (600 MHz, DMSO-d₆) δ 8.85 (s, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.27(d, J=2.0 Hz, 1H), 7.24 (dd, J=8.5, 2.4 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H),7.12 (dd, J=8.2, 1.9 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.71 (dd, J=15.4,6.5 Hz, 1H), 5.14-5.00 (m, 1H), 4.02 (d, J=12.0 Hz, 1H), 3.97 (d, J=12.1Hz, 1H), 3.77 (d, J=8.7 Hz, 2H), 3.59 (d, J=18.3 Hz, 2H), 3.54 (d,J=14.2 Hz, 1H), 3.39 (dd, J=14.4, 5.4 Hz, 1H), 3.26 (d, J=14.4 Hz, 2H),3.03 (s, 3H), 2.86-2.78 (m, 1H), 2.77-2.70 (m, 2H), 2.45-2.38 (m, 1H),2.34-2.30 (m, 1H), 2.08-1.93 (m, 5H), 1.88-1.80 (m, 3H), 1.79-1.71 (m,2H), 1.63-1.44 (m, 3H).

Example 101(3R,6R,11R,24S)-6′-Chloro-10-methyl-17,17-dioxo-spiro[8,22-dioxa-17-thia-1,10,14,16-tetrazapentacyclo[16.7.2.111,14.03,6.021,26]octacosa-18(27),19,21(26)-triene-24,1′-tetralin]-9,15-dione

Step 1:[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylcarbonochloridate

To a solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(300.0 mg, 0.42 mmol, Intermediate 3 Step 2) in DCM (5 mL) was addedtriphosgene (62 mg, 0.21 mmol) and pyridine (0.03 mL, 0.42 mmol) at r.t.The reaction was stirred for 1 h. Water was added and extracted withDCM. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was used directlywithout further purification.

Step 2: tert-butyl(3R)-3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxycarbonylamino]pyrrolidine-1-carboxylate

To a solution of[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylcarbonochloridate (161 mg, 0.21 mmol) in MeCN (2 mL) was added potassiumcarbonate (285 mg, 2.07 mmol) and tert-butyl(3R)-3-(methylamino)pyrrolidine-1-carboxylate (124 mg, 0.62 mmol). Thereaction mixture was stirred at r.t. for 2 d. After the reaction wascompleted, Water was added and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column with EtOAc in Hexane (0-50%) to afford tert-butyl(3R)-3-[[(1R,2R)-2-[[rac-(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxycarbonylamino]pyrrolidine-1-carboxylate(105 mg, 54% yield)

Step 3:[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylN-methyl-N-[(3R)-pyrrolidin-3-yl]carbamate

To a solution of tert-butyl(3R)-3-[methyl-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxycarbonyl]amino]pyrrolidine-1-carboxylate(105.0 mg, 0.11 mmol) in DCM (0.50 mL) was added 2,2,2-trifluoroaceticacid (1.0 mL, 13.07 mmol). The reaction mixture was stirred at r.t.overnight. The mixture was neutralized by sat. NaHCO₃ aq. and extractedwith DCM. The combined organic layers were dried over Na₂SO₄, filteredand evaporated under reduced pressure. The residue was purified byprep-HPLC with MeCN/H₂O to afford[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylN-methyl-N-[(3R)-pyrrolidin-3-yl]carbamate (47.5 mg, 70.78% yield).

Step 4:[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylN-methyl-N-[(3R)-1-(pyrrole-1-carbonyl)pyrrolidin-3-yl]carbamate

To a solution of[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylN-methyl-N-[(3R)-pyrrolidin-3-yl]carbamate (47.4 mg, 0.08 mmol) in THF(0.50 mL) was added 1,1′-carbonyldiimidazole (14.0 mg, 0.09 mmol). Thereaction was heated to 55° C. for 30 min. The resulting mixture wasquenched with water and extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered and evaporated under reducedpressure to afford the crude product which was used directly in nextstep without further purification.

Step 5:(3R,6R,11R,24S)-6′-chloro-10-methyl-17,17-dioxo-spiro[8,22-dioxa-17-thia-1,10,14,16-tetrazapentacyclo[16.7.2.111,14.03,6.021,26]octacosa-18(27),19,21(26)-triene-24,1′-tetralin]-9,15-dione

To a solution of[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methylN-methyl-N-[(3R)-1-(pyrrole-1-carbonyl)pyrrolidin-3-yl]carbamate (52.2mg, 0.07 mmol) in MeCN (0.50 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (34.24 mg, 0.22 mmol). Thereaction was heated to 85° C. overnight. The reaction was quenched withwater (2 mL) and the mixture was extracted with DCM (2×2 mL). Thecombined organic layers were dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The residue was purified by prep-HPLC on C18column (30×250 mm, 10 μm) using MeCN/H₂O (20% to 100%) to afford(3R,6R,11R,24S)-6′-chloro-10-methyl-17,17-dioxo-spiro[8,22-dioxa-17-thia-1,10,14,16-tetrazapentacyclo[16.7.2.111,14.03,6.021,26]octacosa-18(27),19,21(26)-triene-24,1′-tetralin]-9,15-dione(7 mg, 14% yield). LC-MS: calc. for C₃₁H₃₈ClN₄O₆S [M+H]⁺:m/z=629.21/631.21; Found: 628.9/631.1. ¹H NMR (400 MHz, DMSO-d₆) δ 7.66(d, J=8.4 Hz, 1H), 7.30-7.21 (m, 1H), 7.19 (d, J=2.1 Hz, 1H), 7.11 (d,J=18.0 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.57 (s, 1H), 4.21-3.90 (m, 4H),3.88-3.29 (m, 10H), 3.23 (dd, J=25.3, 21.5 Hz, 3H), 2.87-2.56 (m, 4H),2.40-1.74 (m, 6H), 1.58 (d, J=47.6 Hz, 3H).

Example 102(3R,6R,11R,24S)-6′-Chloro-17,17-dioxo-spiro[8,22-dioxa-17-thia-1,10,14,16-tetrazapentacyclo[16.7.2.111,14.03,6.021,26]octacosa-18(27),19,21(26)-triene-24,1′-tetralin]-9,15-dione

This compound was prepared using procedures analogous to those describedfor Example 101 Step 2-5 using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate to replace(3R)-3-(methylamino)pyrrolidine-1-carboxylate in Step 2. LC-MS calc. forC₃₀H₃₆ClN₄O₆S [M+H]⁺: 615.22/617.22; Found: 614.9/616.7. ¹H NMR (400MHz, DMSO-d₆) δ 7.65 (d, J=8.1 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.20 (s,1H), 7.12 (s, 1H), 6.97 (dd, J=16.3, 8.5 Hz, 1H), 6.82 (d, J=8.7 Hz,1H), 6.57 (s, 1H), 4.22 (s, 1H), 4.05 (s, 1H), 3.80 (d, J=16.1 Hz, 1H),3.71 (d, J=2.6 Hz, 1H), 3.12 (s, 2H), 2.84-2.62 (m, 2H), 2.37-2.27 (m,1H), 1.68 (ddd, J=134.6, 64.0, 36.5 Hz, 10H).

Example 103(3R,6R,11S,24S)-6′-Chloro-10-methyl-17,17-dioxo-spiro[8,22-dioxa-17λ{circumflexover ( )}6-thia-1,10,14,16-tetrazapentacyclo[16.7.2.1{circumflex over( )}11,14.0{circumflex over ( )}3,6.0{circumflex over( )}21,26]octacosa-18,20,26-triene-24,1′-tetralin]-9,15-dione

This compound was prepared using procedures analogous to those describedfor Example 101 Step 2-5 using(3S)-3-(methylamino)pyrrolidine-1-carboxylate to replace(3R)-3-(methylamino)pyrrolidine-1-carboxylate in Step 2. LC-MS: calc.for C₃₁H₃₈ClN₄O₆S [M+H]⁺: m/z=629.2/631.2; Found: 628.9/631.1. ¹H NMR(600 MHz, MeOH-d₄) δ 7.72 (d, J=8.5 Hz, 1H), 7.32 (d, J=6.4 Hz, 1H),7.21-7.18 (m, 1H), 7.17 (s, 1H), 7.14 (s, 1H), 6.96 (d, J=8.0 Hz, 1H),4.24-4.03 (m, 6H), 3.71 (s, 2H), 3.62-3.36 (m, 3H), 2.94 (s, 2H), 2.81(dt, J=16.9, 13.1 Hz, 3H), 2.70 (s, 1H), 2.46 (s, 1H), 2.22-2.09 (m,3H), 2.00 (s, 2H), 1.91 (d, J=6.6 Hz, 3H), 1.67 (d, J=28.3 Hz, 3H), 1.33(d, J=27.8 Hz, 2H).

Example 104(3R,6R,24S)-6′-Chloro-17,17-dioxo-spiro[8,22-dioxa-17-thia-1,11,16-triazapentacyclo[16.7.2.19,13.03,6.021,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one(PRT1001203)

Step 1:(3S)-5-[[2-(bromomethyl)cyclobutyl]methyl]-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of CBr₄ (388.35 mg, 1.17 mmol) in DCM (25 mL) under anatmosphere of nitrogen was added triphenylphosphine (307 mg, 1.17 mmol)and stirred for 30 mins. To this was added the(3S)-6′-chloro-5-[[2-(hydroxymethyl)cyclobutyl]methyl]-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Example 18, Step 2, 420 mg, 0.59 mmol). The reaction was stirred atr.t. for 14 h. The reaction mixture was concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column using 0-30% EtOAc in hexane to give(3S)-5-[[2-(bromomethyl)cyclobutyl]methyl]-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(300 mg, 65% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.67 (d, J=8.5 Hz, 1H),7.24-7.08 (m, 3H), 7.06-6.96 (m, 6H), 6.84-6.75 (m, 4H), 4.29 (d, J=5.7Hz, 4H), 4.11 (d, J=1.7 Hz, 2H), 3.79 (d, J=7.5 Hz, 8H), 3.70-3.55 (m,2H), 3.40-3.19 (m, 4H), 2.78 (d, J=12.2 Hz, 2H), 2.46-2.29 (m, 2H),2.05-1.80 (m, 4H), 1.70-1.48 (m, 2H).

Step 2: Methyl 2-[5-[[(JR,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-3-pyridyl]acetate

To(3S)-5-[[2-(bromomethyl)cyclobutyl]methyl]-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(300.0 mg, 0.38 mmol) in MeCN (20 mL) was added the potassium carbonate(215 mg, 1.54 mmol), and methyl 2-(5-hydroxy-3-pyridyl)acetate (128 mg,0.77 mmol). The reaction was heated at 80° C. overnight, filtered andconcentrated under reduced pressure The residue was purified by flashchromatography on a silica gel column using 0-40% EtOAc in hexane togive methyl2-[5-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-3-pyridyl]acetate(170 mg, 51% yield). LC-MS calc. for C₄₈H₅₃ClN₃O₈S [M+H]⁺: m/z=866.3;found 866.5. ¹H NMR (500 MHz, CDCl₃) δ 8.13 (s, 2H), 7.68 (d, J=8.4 Hz,1H), 7.47 (s, 1H), 7.19 (dd, J=2.3, 8.5 Hz, 1H), 7.15-7.10 (m, 2H), 7.05(d, J=2.1 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.93 (d, J=8.7 Hz, 4H), 6.76(d, J=8.6 Hz, 4H), 4.13 (d, J=15.2 Hz, 8H), 3.99-3.90 (m, 2H), 3.78 (s,7H), 3.71 (s, 4H), 3.64 (s, 4H), 3.34-3.19 (m, 2H), 2.79 (s, 2H), 2.49(s, 2H).

Step 3: Methyl2-[5-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-3-pyridyl]acetate

To methyl2-[5-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-3-pyridyl]acetate(170 mg, 0.20 mmol) in DCM (3 mL) was added the 2,2,2-trifluoroaceticacid (TFA) (1.5 mL). The reaction stirred at r.t. for 16 h. The reactionwas concentrated under vacuum, extracted with DCM, the organic layer waswashed with water, saturated sodium bicarbonate, and dried over sodiumsulfate. The DCM layer was filtered, concentrated under reducedpressure, and purified by flash chromatography on a silica gel columnusing 0-10% methanol in DCM to give methyl2-[5-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-3-pyridyl]acetate(99 mg, 80.6% yield).

Step 4:2-[5-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-3-pyridyl]aceticacid

To methyl2-[5-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-3-pyridyl]acetate(99.0 mg, 0.16 mmol) in THF (3 mL) and water (3 mL) was added thelithium hydroxide (18.0 mg, 0.72 mmol) and stirred at r.t. for 2 h. Thereaction mixture was concentrated and the residue neutralized with 0.25N HCl, extracted with ethyl acetate. The combined organic layers werewashed with water, brine, dried over sodium sulfate, filtered andconcentrated to give2-[5-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-3-pyridyl]aceticacid (92 mg, 80% yield). LC-MS calc. for C₃₃H₃₅ClF₃N308S [M+H]⁺:m/z=612.2; found 612.4.

Step 5:(3R,6R,24S)-6′-chloro-17,17-dioxo-spiro[8,22-dioxa-17-thia-1,11,16-triazapentacyclo[16.7.2.19,13.03,6.021,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one

To2-[5-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-3-pyridyl]aceticacid (72.0 mg, 0.12 mmol) in DCM (9 mL) and DMF (1 mL) was added theEDCI (67 mg, 0.35 mmol) and DMAP (67 mg, 0.55 mmol) and stirred at r.t.for 16 h. The reaction was diluted with water, extracted with ethylacetate. The ethyl acetate layer was washed with water brine, dried oversodium sulfate, filtered and concentrated under reduced pressure Theresidue was purified by flash chromatography on a silica gel columnusing 0-15% MeOH in DCM to give(3R,6R,24S)-6′-chloro-17,17-dioxo-spiro[8,22-dioxa-17-thia-1,11,16-triazapentacyclo[16.7.2.19,13.03,6.021,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one(20 mg, 28% yield). LC-MS calc. for C₃₁H₃₃ClN₃O₅S [M+H]⁺: m/z=594.2;Found 594.3. ¹H NMR (500 MHz, MeCN-d₃) δ 8.04 (d, J=2.6 Hz, 1H), 7.90(d, J=1.7 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.30 (t, J=2.2 Hz, 1H),7.23-7.07 (m, 3H), 6.98 (d, J=2.2 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H),4.17-3.98 (m, 4H), 3.53 (d, J=14.5 Hz, 1H), 3.45-3.20 (m, 7H), 2.84-2.69(m, 3H), 2.55 (d, J=12.0 Hz, 3H), 1.90-1.47 (m, 5H).

Example 105(3R,6R,24S)-6′-Chloro-11-(2-morpholinoethoxy)-17,17-dioxo-spiro[8,22-dioxa-17-thia-1,16-diazapentacyclo[16.7.2.19,13.03,6.021,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one

Step 1: methyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-5-hydroxy-phenyl]acetate

This compound was prepared using procedure analogous to that describedfor Example 18 Step 3 using methyl 2-(3,5-dihydroxyphenyl)acetate toreplace methyl 3-hydroxyphenylacetate. R_(f)=0.73 (1:1 hexanes:EtOAc).

Step 2: methyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-5-(2-morpholinoethoxy)phenyl]acetate

A mixture of methyl2-[3-hydroxy-5-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]phenyl]acetate(72 mg, 0.08 mmol), and triphenylphosphine (37.0 mg, 0.14 mmol) wereevacuated and recharged with N₂ (×2). Then N-(2-hydroxyethyl)morpholine(15.0 μL, 0.12 mmol) in DCM (3 mL) was added. To the mixture was added asolution of di-tert-butyl azodicarboxylate (25.0 mg, 0.11 mmol) in DCM(850 μL) dropwise over 2 min at r.t. The reaction mixture was stirred atr.t. overnight. An additional triphenylphosphine (9.0 mg, 0.03 mmol) wasadded, followed by diisopropyl azodicarboxylate (9.0 μL, 0.05 mmol). Themixture was stirred at r.t. for 1 h., concentrated under reducedpressure and purified by flash chromatography on a silica gel columnwith EtOAc in hexanes (10-100%) and then MeOH in DCM (2%) (with 0.2%NH₄OH) to afford methyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-5-(2-morpholinoethoxy)phenyl]acetate(44 mg, 54% yield). LCMS m/z calc. for C₅₅H₆₅ClN₃O₁₀S [M+H]⁺:m/z=994.41; Found: 994.5.

Step 3:(3R,6R,24S)-6′-chloro-11-(2-morpholinoethoxy)-17,17-dioxo-spiro[8,22-dioxa-17-thia-1,16-diazapentacyclo[16.7.2.19,13.03,6.021,26]octacosa-9(28),10,12,18(27),19,21(26)-hexaene-24,1′-tetralin]-15-one

This compound was prepared as TFA salt using procedures analogous tothose described for Example 18 Step 4-6 using methyl2-[3-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]-5-(2-morpholinoethoxy)phenyl]acetate.LCMS m/z calc. for C₃₈H₄₅ClN₃O₇S [M+H]⁺: m/z=722.27; found: 722.5. ¹HNMR (500 MHz, DMSO-d₆) δ 12.05 (s, 1H), 9.94 (s, 1H), 7.60 (d, J=8.6 Hz,1H), 7.27 (dd, J=2.4, 8.5 Hz, 1H), 7.21 (d, J=2.3 Hz, 1H), 7.07 (dd,J=2.1, 8.3 Hz, 1H), 6.92-6.86 (m, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.64 (s,1H), 6.51 (bs, 2H), 6.35 (d, J=2.2 Hz, 1H), 6.28 (s, 1H), 4.21 (q,J=5.0, 6.2 Hz, 2H), 4.11-4.03 (m, 2H), 4.03-3.95 (m, 4H), 3.74-3.65 (m,2H), 3.48 (d, J=7.8 Hz, 1H), 3.41 (t, J=13.7 Hz, 1H), 3.39-3.25 (m, 4H),3.20 (q, J=11.5, 14.9 Hz, 3H), 2.83-2.69 (m, 2H), 2.63 (s, 1H),2.01-1.86 (m, 3H), 1.83-1.73 (m, 3H), 1.60 (q, J=10.4 Hz, 1H), 1.56-1.49(m, 1H).

Example 106(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-15,15-dioxo-spiro[20-oxa-15-thia-1,12,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1:1-but-3-enyl-3-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-urea

To a stirred solution of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(100 mg, 0.19 mmol, Intermediate 8) in MeCN (3 mL) was added TEA (0.1mL, 0.58 mmol) and phenyl chloroformate (0.07 mL, 0.58 mmol). Theresulting mixture was stirred at r.t. for 10 min. LCMS indicated thestarting material was consumed. But-3-en-1-amine (16.5 mg, 0.23 mmol)was then added to the reaction mixture and the resulting solution wasstirred overnight. The reaction was quenched by water (5 mL), extractedwith EtOAc (3×10 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column (12 g) usingEtOAc/Heptanes (2% to 60%) to afford1-but-3-enyl-3-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-urea(91 mg, 76% yield) as a white solid. LC-MS calc. for C₃₂H₄₁ClN₃O₅S[M+H]⁺: m/z=614.25/616.25. Found: 613.9/615.4.

Step 2:(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-15,15-dioxo-spiro[20-oxa-15-thia-1,12,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

A solution of1-but-3-enyl-3-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-urea(91.0 mg, 0.15 mmol) in DCE (100 mL) was bubbled with N₂ for 30 min.Hoveyda-Grubbs II (18.5 mg, 0.03 mmol) was added and the reactionmixture was further bubbled with N₂ for 30 min., and was stirred at 80°C. under N₂ overnight. The reaction was concentrated under reducedpressure, and the residue was purified by flash chromatography on asilica gel column (12 g) using EtOAc/Heptanes (2% to 60%). The desiredfractions were collected, concentrated under reduced pressure, andfurther purified by Prep-HPLC on C18 column (30×250 mm, 10 m) with 20 to100% CH3CN/H₂O (t_(R)=23 min) to afford(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-15,15-dioxo-spiro[20-oxa-15-thia-1,12,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(38 mg, 43% yield) as a white solid. LC-MS calc. for C₃₀H₃₇ClN₃O₅S[M+H]⁺: m/z=586.21/588.21; Found 586.1/587.9. ¹H NMR (600 MHz, CDCl₃) δ7.68 (d, J=8.5 Hz, 1H), 7.18 (dt, J=8.7, 2.4 Hz, 1H), 7.08 (d, J=2.1 Hz,1H), 7.02 (s, 1H), 6.99 (s, 1H), 6.96 (d, J=8.3 Hz, 1H), 5.88 (dt,J=14.2, 6.5 Hz, 1H), 5.48 (dd, J=15.7, 8.3 Hz, 1H), 4.09 (s, 2H), 3.80(d, J=14.6 Hz, 1H), 3.67 (d, J=15.0 Hz, 1H), 3.49 (t, J=8.2 Hz, 2H),3.42-3.30 (m, 2H), 3.26 (s, 3H), 3.02 (dd, J=15.1, 10.7 Hz, 1H),2.89-2.67 (m, 2H), 2.57 (d, J=10.2 Hz, 1H), 2.38 (s, 2H), 2.29-2.12 (m,1H), 2.10-1.91 (m, 3H), 1.84 (d, J=12.9 Hz, 1H), 1.67 (p, J=9.5 Hz, 3H),1.42 (t, J=13.1 Hz, 1H), 1.39-1.21 (m, 2H).

Example 107(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,12,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 106 using N-methylbut-3-en-1-amine hydrochloride to replacebut-3-en-1-amine in Step 1. LC-MS calc. for C₃₁H₃₉ClN₃O₅S [M+H]⁺:m/z=600.22/602.22; Found 600.1/602.0. ¹H NMR (600 MHz, CDCl₃) δ 7.69 (d,J=8.5 Hz, 1H), 7.52-7.30 (m, 2H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.08 (t,J=1.6 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 5.53-5.11 (m, 2H), 4.13 (d,J=12.2 Hz, 1H), 4.03 (d, J=12.1 Hz, 1H), 3.76-3.58 (m, 3H), 3.31 (d,J=14.6 Hz, 1H), 3.17-3.00 (m, 5H), 2.85 (s, 3H), 2.82-2.68 (m, 3H),2.43-2.15 (m, 3H), 2.02-1.94 (m, 1H), 1.91-1.69 (m, 5H), 1.43 (q,J=16.1, 11.8 Hz, 2H), 1.36-1.18 (m, 1H).

Example 108(3R,6R,7R,8E,21S)-6′-Chloro-7-methoxy-11-methyl-14,14-dioxo-spiro[19-oxa-14-thia-1,11,13-triazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-one

This compound was prepared using procedures analogous to those describedfor Example 106 using N-methylprop-2-en-1-amine hydrochloride to replacebut-3-en-1-amine in Step 1. LC-MS: calc. for C₃₀H₃₇ClN₃O₅S [M+H]⁺:m/z=586.2/588.2; Found: 586.0/587.8. ¹H NMR (600 MHz, CDCl₃) δ 7.69 (d,J=8.5 Hz, 1H), 7.48-7.32 (m, 1H), 7.22-7.13 (m, 1H), 7.07 (d, J=2.2 Hz,1H), 7.01 (s, 1H), 6.93 (s, 1H), 5.85 (d, J=16.0 Hz, 1H), 5.69 (s, 1H),4.25 (d, J=18.4 Hz, 1H), 4.07 (s, 2H), 3.76 (d, J=14.4 Hz, 3H), 3.61 (t,J=7.0 Hz, 1H), 3.32-3.22 (m, 4H), 3.13-2.95 (m, 3H), 2.85-2.67 (m, 2H),2.52 (t, J=8.9 Hz, 1H), 2.09-1.97 (m, 2H), 1.91 (s, 2H), 1.87-1.76 (m,1H), 1.66 (p, J=9.4 Hz, 2H), 1.57-1.46 (m, 1H), 1.40 (t, J=13.0 Hz, 1H),1.28-1.22 (m, 1H).

Example 109(3R,6R,8E,22S)-6′-Chloro-7-hydroxy-7-[(4-isopropylpiperazin-1-yl)methyl]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1:(3R,6R,8E,22S)-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7,13-dione

To a solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(175 mg, 0.29 mmol, Example 32) in DCM (17 mL) was added Dess-Martinperiodinane (144 mg, 0.34 mmol) at 0° C. (ice-water bath). The mixturewas stirred at r.t. for 30 min., and then quenched with 10% sodiumthiosulfate (5 mL) and stirred for additional 30 min. The resultingmixture was extracted with DCM (10 mL×2). The combined organic layerswere washed with saturated NaHCO₃(10 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified byflash chromatography on a silica gel column with EtOAc/Heptanes (5-90%)to afford the desired product(3R,6R,8E,22S)-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7,13-dione(100 mg, 57% yield). LC-MS calc. for C₃₁H₃₆ClN₂O₆S [M+H]⁺:m/z=599.19/601.19; Found 599.5/601.5.

Step 2:(3R,6R,8E,22S)-6′-chloro-7,7-(I-oxa-ethylene)-12,12-dimethyl-1S,15-dioxo-spiro[11,20-dioxa-1S-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

To a solution of(3R,6R,8E,22S)-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7,13-dione(100 mg, 0.17 mmol) in DMSO (8 mL) and THF (2 mL) was addedtrimethylsulfonium iodide (51 mg, 0.25 mmol), followed by potassiumt-butoxide (1.OM in THF) (46 mg, 0.42 mmol) at 0° C. in ice-water bath.The mixture was then stirred at r.t. for 3 h. The reaction was monitoredby LC-MS. The reaction was quenched with 1 drop acetic acid and stirredfor 1 min. The mixture was poured into ethyl acetate (20 mL) and washedwith water (20 mL). The aqueous layer was extracted with EA (20 mL×2).The combined organic layers were washed with water (50 mL), brine (50mL) and dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column with EtOAc/Heptanes (5-90%) to afford the desired product(3R,6R,8E,22S)-6′-chloro-7,7-(1-oxa-ethylene)-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(50 mg, 48% yield). LC-MS calc. for C₃₂H₃₈ClN₂O₆S [M+H]⁺:m/z=613.21/615.20; Found 613.7/615.7.

Step 3:(3R,6R,8E,22S)-6′-chloro-7-hydroxy-7-[(4-isopropylpiperazin-1-yl)methyl]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-1S-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

To a solution of(3R,6R,8E,22S)-6′-chloro-7,7-(1-oxa-ethylene)-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(10.0 mg, 0.02 mmol) and 1-isopropylpiperazine (3.1 mg, 0.02 mmol) inTHF (2 mL) was added potassium t-butoxide (1.0 M in THF) (3.6 mg, 0.03mmol). The mixture was stirred at 65° C. for 3 d. and monitored byLC-MS. The reaction mixture was neutralized with 1-2 drops of 2 N HCl inethyl acetate. The solvent was then removed and the residue was purifiedthrough Prep-HPLC on C18 column to afford(3R,6R,8E,22S)-6′-chloro-7-hydroxy-7-[(4-isopropylpiperazin-1-yl)methyl]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(2.8 mg, 23% yield) as a white solid. LC-MS calc. for C₃₉H₅₄ClN₄O₆S[M+H]⁺: m/z=741.34/743.33; Found 741.8/743.8.

Example 110(3R,6R,22S)-6′-Chloro-8,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-thia-1,8,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-16(25),17,19(24)-triene-22,1′-tetralin]-7,13-dione

Step 1:2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-2-methyl-propanoic acid

To a stirred solution of 2-bromo-2-methyl-propanoic acid (500 mg, 2.99mmol) in MeCN (3 mL) was added tert-butylN-(2-hydroxyethyl)-N-methyl-carbamate (786 mg, 4.49 mmol) and DIPEA(1.15 mL, 6.59 mmol) at 40° C. The resulting solution was stirred at 40°C. for 3 h. LC-MS analysis indicated the reaction was complete. Thereaction mixture was adjusted with 1 N HCl to pH 1-2, and then extractedwith EtOAc (2×20 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-2-methyl-propanoic acid(160 mg, 20% yield) as a colorless oil. LC-MS calc. for C₁₂H₂₂NO₅[M−H]⁻: m/z=260.3; Found: 260.2.

Step 2:(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylicacid

To a suspension of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(1450.0 mg, 2.03 mmol, Intermediate 3 Step 3) in 1-butanol (5 mL) and2-methylbut-2-ene (5.0 mL, 47.2 mmol) was added sodium chlorite (458 mg,4.05 mmol) and the solution of sodium phosphate monobasic monohydrate(559 mg, 4.05 mmol) in water (5 mL). The reaction was stirred at r.t.for 3 h. LC-MS showed reaction was completed. The reaction was quenchedwith 10% Na₂S₂O₃ aq. (5 mL) and the mixture was extracted with EtOAc(2×2 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated under reduced pressure to afford the crude product (500mg) which was used directly in next step reaction without furtherpurification.

Step 3: methyl(1R,2R)-2-[[rac-(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylate

To a solution of(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylicacid (500 mg, 0.68 mmol) in DMF (5 mL) was added iodomethane (116 mg,0.82 mmol) and potassium carbonate (141 mg, 1.03 mmol). The reaction wasstirred overnight and then quenched with water (20 mL), and extractedwith MTBE (2×10 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was used without further purification.

Step 4: methyl(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylate

To a solution of methyl(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylate(850 mg, 1.14 mmol) in DCM (2 mL) was added anisole (0.5 mL, 4.6 mmol)and 2,2,2-trifluoroacetic acid (TFA) (2.0 mL, 26.14 mmol). The reactionwas stirred at r.t. overnight. Upon completion of the reaction, themixture was concentrated under reduced pressure. The residue wasre-dissolved in DCM and washed with sat. Na₂CO₃ aq. The organic layerwas dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the crude product which was used without further purification.

Step 5: methyl(1R,2R)-2-[[(3S)-7-[[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-2-methyl-propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylate

To a stirred solution of methyl(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl](50 mg, 0.10 mmol) in DCM (1 mL) was added DMAP (48 mg, 0.40 mmol) andEDCI (38 mg, 0.20 mmol) at 20° C. The resulting solution was stirred at20° C. for 3 h. LCMS analysis indicated the reaction was complete. Thereaction mixture was quenched with 1 N HCl solution and extracted withEtOAc (5 mL×3). The combined organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure The residuewas purified by flash chromatography on a silica gel column usingEtOAc/Heptanes (5-90%) to afford methyl(1R,2R)-2-[[(3S)-7-[[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-2-methyl-propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylate(37 mg, 50% yield) as a light orange solid. LC-MS calc. forC37H₅₁ClN₃O₉S [M+H]⁺: m/z=748.3/750.3; Found: 748.5/750.3.

Step 6: methyl(1R,2R)-2-[[(3S)-6′-chloro-7-[[2-methyl-2-[2-(methylamino)ethoxy]propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylate

To a solution of methyl(1R,2R)-2-[[(3S)-7-[[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-2-methyl-propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylate(40 mg, 0.05 mmol) in DCM (0.50 mL) was added phosphoric acid (0.67 mL,11 mmol). The resulting solution was vigorously stirred at 40° C. for 3h. LCMS analysis indicated the reaction was complete. The reactionmixture was quenched with 1 M NaOH aqueous solution to pH 8 andextracted with 2×4 mL DCM. The combined organic layers were concentratedunder reduced pressure to afford methyl(1R,2R)-2-[[(3S)-6′-chloro-7-[[2-methyl-2-[2-(methylamino)ethoxy]propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylate(19 mg, 55% yield) as a white solid. LC-MS calc. for C₃₂H₄₃ClN₃O₇S[M+H]⁺: m/z=648.2/650.2; Found: 648.3/650.3.

Step 7:(1R,2R)-2-[[(3S)-6′-chloro-7-[[2-methyl-2-[2-(methylamino)ethoxy]propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylicacid

To a solution of methyl(1R,2R)-2-[[(3S)-6′-chloro-7-[[2-methyl-2-[2-(methylamino)ethoxy]propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylate(19.0 mg, 0.03 mmol) in methanol (0.50 mL) and THF (0.50 mL) was addedlithium hydroxide monohydrate (3.7 mg, 0.09 mmol) in water (0.50 mL).The resulting solution was stirred at 40° C. for 2 h. LCMS analysisindicated the reaction was complete. The reaction mixture was quenchedwith 1 M HCl aqueous solution to pH 5-6 and extracted with EtOAc (2×10mL). The combined organic layers were concentrated under reducedpressure to afford(1R,2R)-2-[[(3S)-6′-chloro-7-[[2-methyl-2-[2-(methylamino)ethoxy]propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylicacid (16 mg, 86% yield) as a white solid. LC-MS calc. for C₃₁H₄₁ClN₃O₇S[M+H]⁺: m/z=634.2/636.2; Found: 634.6/636.7.

Step 8:(3R,6R,22S)-6′-chloro-8,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-thia-1,8,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-16(25),17,19(24)-triene-22,1′-tetralin]-7,13-dione

To a solution of(1R,2R)-2-[[(3S)-6′-chloro-7-[[2-methyl-2-[2-(methylamino)ethoxy]propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarboxylicacid (16 mg, 0.03 mmol) in DMF (5 mL) was added HATU (2.1 mg, 0.05 mmol)and DIPEA (0.01 mL, 0.05 mmol). The resulting solution was stirred at20° C. for 1 h. LCMS analysis indicated the reaction was complete. Thereaction mixture was quenched with water and extracted with EtOAc (2×10mL). The combined organic layers were concentrated under reducedpressure and the residue was purified by prep-HPLC on C18 column (30×250mm, 10 m) using MeCN/H₂O (20 to 100%) to afford(3R,6R,22S)-6′-chloro-8,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-thia-1,8,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-16(25),17,19(24)-triene-22,1′-tetralin]-7,13-dione(4 mg, 25% yield) as a white solid. LC-MS calc. for C₃₁H₃₉ClN₃₀₆S[M+H]⁺: m/z=616.2/618.2; Found 616.6/618.6. ¹H NMR (300 MHz, CDCl₃) δ7.74 (d, J=8.5 Hz, 1H), 7.51-7.31 (m, 2H), 7.22-7.04 (m, 2H), 6.94 (d,J=8.4 Hz, 1H), 4.10 (s, 2H), 4.03-3.89 (m, 1H), 3.89-3.77 (m, 1H),3.73-3.63 (m, 1H), 3.56 (t, J=6.5 Hz, 1H), 3.29 (d, J=14.5 Hz, 2H), 3.11(s, 5H), 2.77 (q, J=5.5, 5.0 Hz, 2H), 2.30-2.15 (m, 1H), 2.06-1.67 (m,9H), 1.41 (s, 3H), 1.34 (s, 3H).

Example 111(3R,6R,7S,8E,22S)-6′-Chloro-7-methoxy-15,15-dioxo-spiro[[11,20]dioxa[15]thia-1,14-diazatetracyclo[14.7.2.03,6.019,24-]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and 2-(allyloxy)acetic acid in Step 3. LC-MS calc. forC₃₀H₃₆ClN₂O₆S [M+H]⁺: m/z=587.19/589.19; Found: 586.8/588.9. ¹H NMR (600MHz, DMSO-d₆) δ 12.01 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.29 (dd, J=8.3,2.1 Hz, 1H), 7.24 (dd, J=8.5, 2.4 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.10(d, J=2.2 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 5.43 (ddt, J=15.6, 7.6, 1.4Hz, 1H), 5.20-5.09 (m, 1H), 4.13 (d, J=12.0 Hz, 1H), 4.06 (d, J=12.0 Hz,1H), 4.01-3.90 (m, 4H), 3.55-3.47 (m, 2H), 3.39 (dd, J=7.5, 3.1 Hz, 1H),3.20-3.12 (m, 1H), 3.05 (s, 3H), 2.80-2.73 (m, 2H), 2.02 (ddd, J=14.2,6.4, 2.8 Hz, 1H), 1.91 (ddt, J=11.2, 7.6, 3.8 Hz, 1H), 1.89-1.80 (m,2H), 1.79-1.71 (m, 2H), 1.66 (ddd, J=13.8, 10.3, 3.2 Hz, 1H), 1.58-1.50(m, 1H), 1.30-1.20 (m, 3H).

Example 112(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-15,15-dioxo-spiro[[11,20]dioxa[15]thia-1,14-diazatetracyclo[14.7.2.03,6.019,24-]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and 2-(allyloxy)acetic acid in Step 3. LC-MS calc. forC₃₀H₃₆ClN₂O₆S [M+H]⁺: m/z=587.19/589.19; Found: 586.8/589.0. ¹H NMR (600MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.26-7.21 (m, 1H), 7.13 (d, J=8.3Hz, 1H), 7.07 (s, 1H), 6.83 (d, J=63.8 Hz, 1H), 6.05 (s, 1H), 5.34 (qd,J=11.1, 6.0 Hz, 1H), 5.17 (dd, J=99.9, 13.5 Hz, 1H), 4.52 (s, 1H),4.19-3.88 (m, 4H), 3.78 (dt, J=31.6, 15.8 Hz, 2H), 3.34 (s, 3H), 3.28(d, J=14.7 Hz, 1H), 3.00 (dd, J=29.7, 15.2 Hz, 1H), 2.83-2.68 (m, 2H),2.64 (s, 1H), 2.33 (d, J=31.7 Hz, 2H), 2.08-1.95 (m, 3H), 1.74-1.54 (m,3H), 1.34 (dd, J=28.1, 12.4 Hz, 3H).

Example 113[(3R,6R,7S,8E,12S,22S)-6′-Chloro-12-methyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]acetate

Step 1: (2S)-2-allyloxypropanoic acid

This compound was prepared using procedures analogous to those describedfor Example 28 Step 1-2 using ethyl (2S)-2-hydroxypropanoate to replacemethyl 1-hydroxycyclopropanecarboxylate in Step 1. TLC R_(f)=0.25(EA:Hep=2:1).

Step 2:[(3R,6R,7S,8E,12S,22S)-6′-chloro-12-methyl-13,15,15-trioxo-spiro[11,20-dioxa-1S-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]acetate

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using[(1S)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetate (Intermediate 5) and (2S)-2-allyloxypropanoic acid in Step 3.LC-MS calc. for C₃₂H₃₈ClN₂O₇S [M+H]⁺: m/z=629.20/631.20; Found:629.0/630.8. ¹H NMR (600 MHz, CDCl₃) δ 8.95 (s, 1H), 7.66 (d, J=8.5 Hz,1H), 7.55-7.48 (m, 1H), 7.17 (dd, J=8.5, 2.3 Hz, 1H), 7.12 (d, J=2.2 Hz,1H), 7.09 (d, J=2.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 5.59 (q, J=3.7 Hz,2H), 5.41-5.28 (m, 1H), 5.21 (t, J=4.3 Hz, 1H), 4.39-4.29 (m, 1H), 4.24(d, J=12.2 Hz, 1H), 4.13 (d, J=12.2 Hz, 1H), 3.83-3.70 (m, 2H), 3.66 (d,J=14.6 Hz, 1H), 3.48-3.31 (m, 2H), 3.23 (dd, J=15.0, 8.1 Hz, 1H),2.87-2.72 (m, 3H), 2.53 (dt, J=13.7, 8.8 Hz, 1H), 2.07 (s, 3H),2.07-1.72 (m, 5H), 1.60 (td, J=18.9, 17.8, 11.1 Hz, 2H), 1.41 (d, J=6.8Hz, 3H).

Example 114(3R,6R,7R,8E,12S,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (2S)-2-allyloxypropanoic acid (Example 113 Step 1)in Step 3. LC-MS calc. for C₃₃H₃₈ClN₂O₆S [M+H]⁺: m/z=601.2/603.2; Found:601.0/602.8. ¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1H), 7.63 (dd,J=30.8, 26.0 Hz, 1H), 7.29 (dd, J=8.5, 2.2 Hz, 1H), 7.26-7.21 (m, 3H),7.05 (d, J=7.4 Hz, 1H), 5.38-5.20 (m, 1H), 4.21 (d, J=12.9 Hz, 1H), 4.11(d, J=12.2 Hz, 1H), 4.01 (d, J=12.3 Hz, 1H), 3.80-3.52 (m, 4H),3.07-2.94 (m, 3H), 2.87-2.65 (m, 3H), 2.33 (dd, J=11.1, 9.2 Hz, 1H),2.05-1.92 (m, 1H), 1.88-1.54 (m, 6H), 1.42 (dd, J=22.3, 11.3 Hz, 1H),1.30-1.21 (m, 5H) ppm.

Example 115(3R,6R,7R,8E,12R,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: (2R)-2-allyloxypropanoic acid

1 This compound was prepared using procedures analogous to thosedescribed for Example 28 Step 1-2 using ethyl (2R)-2-hydroxypropanoateto replace methyl 1-hydroxycyclopropanecarboxylate in Step 1. TLCR_(f)=0.3 (50% EA in Hep).

Step 2:(3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-12-methyl-1S,15-dioxo-spiro[11,20-dioxa-1S-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (2R)-2-allyloxypropanoic acid in Step 3. LC-MScalc. for C₃₃H₃₈ClN₂O₆S [M+H]⁺: m/z=601.2/603.2; Found: 600.8/603.0. ¹HNMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 7.67 (d, J=8.6 Hz, 1H),7.30-7.23 (m, 2H), 7.19 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.3 Hz, 2H),5.70-5.61 (m, 1H), 5.13 (dd, J=15.6, 8.0 Hz, 1H), 4.25 (d, J=12.1 Hz,1H), 4.06 (d, J=12.1 Hz, 1H), 3.97 (dd, J=12.8, 6.2 Hz, 2H), 3.78 (dd,J=14.4, 6.8 Hz, 1H), 3.52 (d, J=14.4 Hz, 1H), 3.39 (t, J=6.5 Hz, 2H),3.30 (d, J=7.3 Hz, 2H), 3.09 (s, 2H), 2.84-2.65 (m, 3H), 2.30 (dd,J=16.0, 10.6 Hz, 2H), 2.06-1.96 (m, 2H), 1.95-1.76 (m, 4H), 1.62-1.42(m, 4H), 1.24 (d, J=6.6 Hz, 3H).

Example 116(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[[20]oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

Step 1: ethyl 1-(tert-butoxycarbonylamino)cyclobutanecarboxylate

To a solution of ethyl 1-aminocyclobutanecarboxylate hydrochloride (1.00g, 5.57 mmol) and sodium bicarbonate (1.43 g, 16.7 mmol) in THF (5 mL)and water (5 mL) was added di-tert butyl dicarbonate (1.46 g, 6.68mmol). The resulting mixture was stirred at r.t. for 10 min. and brieflyheated in a hot water bath at 50° C. for 10 min. diluted with water, andextracted with MTBE. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure toafford the crude product which was used without further purifications.LC-MS calc. for C₁₂H₂₂NO₄ [M+H]⁺: m/z=244.15; Found 244.0.

Step 2: ethyl 1-[allyl(tert-butoxycarbonyl)amino]cyclobutanecarboxylate

To a suspension of sodium hydride (60%, 446 mg, 11.5 mmol) in DMF (15mL) was added ethyl 1-(tert-butoxycarbonylamino)cyclobutanecarboxylate(1.35 g, 5.57 mmol) in DMF (5 mL) at 0° C. After 20 min., allyl bromide(1.01 g, 8.36 mmol) was added in one portion. The reaction was stirredat ambient temperature overnight, quenched with saturated aqueous NH₄Cland extracted with EtOAc. The combined organic layers were washed withwater and brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column (3% to 8% EtOAc/Hept) to afford ethyl1-[allyl(tert-butoxycarbonyl)amino]cyclobutanecarboxylate (1.42 g, 90%yield) as a colorless oil. TLC (10% EtOAc/Hept) R_(f)=0.48.

Step 3: 1-[allyl(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid

A solution of ethyl1-[allyl(tert-butoxycarbonyl)amino]cyclobutanecarboxylate (1.40 g, 4.94mmol) and lithium hydroxide monohydrate (1.03 g, 24.7 mmol) inMeOH/THF/H₂O (5 mL, 5 mL, 8 mL) was heated at 45° C. overnight. Thereaction was cooled to 0° C., acidified with 2 N HCl, and extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure The residue waspurified by flash chromatography on a silica gel column (10% to 30%EtOAc/Hept) to afford1-[allyl(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid (0.790 g,62.6% yield). LC-MS calc. for C₁₃H₂₀NO₄ [M−H]⁻. m/z=254.14; Found 254.1.

Step 4:(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-5 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and1-[allyl(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid in Step 3.LC-MS calc. for C₃₃H₄₁ClN₃O₅S [M+H]⁺: m/z=626.24/628.24; Found:626.0/628.2. ¹H NMR (600 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H), 7.42 (dd,J=8.6, 2.1 Hz, 1H), 7.26 (app s, 1H, overlapped with CHCl₃), 7.17 (dd,J=8.5, 2.3 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H),5.37-5.24 (m, 2H), 4.11 (d, J=12.1 Hz, 1H), 4.06 (d, J=12.2 Hz, 1H),3.70 (d, J=14.6 Hz, 1H), 3.65 (dd, J=14.4, 7.0 Hz, 1H), 3.40 (dd,J=14.7, 4.3 Hz, 1H), 3.31 (d, J=14.6 Hz, 1H), 3.13 (s, 3H), 3.09 (d,J=5.6 Hz, 1H), 3.02 (dd, J=15.1, 7.1 Hz, 1H), 2.94 (d, J=13.1 Hz, 1H),2.82-2.71 (m, 2H), 2.59 (dqd, J=16.2, 8.8, 8.2, 2.6 Hz, 2H), 2.45 (tt,J=8.4, 3.3 Hz, 1H), 2.28 (d, J=8.1 Hz, 1H), 2.08-1.77 (m, 10H),1.76-1.69 (m, 1H), 1.68-1.60 (m, 1H), 1.44-1.37 (m, 1H).

Example 117(3R,6R,7R,8E,12S,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

Step 1: (2S)-2-[allyl(tert-butoxycarbonyl)amino]propanoic acid

This compound was prepared using procedures analogous to those describedfor Example 116 Step 2-3 using methyl(2S)-2-(tert-butoxycarbonylamino)propanoate to replace ethyl1-(tert-butoxycarbonylamino)cyclobutanecarboxylate in Step 2.

Step 2: tert-butylN-allyl-N-[(1S)-1-methyl-2-oxo-2-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]ethyl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (2S)-2-[allyl(tert-butoxycarbonyl)amino]propanoicacid.

Step 3: tert-butyl(3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylateand tert-butyl(3R,6R,7R,8Z,12S,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 26 Step 4 using tert-butylN-allyl-N-[(1S)-1-methyl-2-oxo-2-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]ethyl]carbamate(81.3 mg, 0.11 mmol) in DCE (110 mL) at 80° C. overnight and purified byflash chromatography on a silica gel column (12 g) with EtOAc/Heptanes(2% to 50%) to afford two products: P1 (the earlier eluted product, 29.8mg, 38.1% yield) and P2 (the latter eluted product, 21.7 mg, 27% yield).

P1 was assigned to tert-butyl(3R,6R,7R,8Z,12S,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylate,and P2 was assigned to tert-butyl(3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylate.

Step 5:(3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

tert-butyl(3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylate(21.7 mg, 0.03 mmol, P2 Step 4) was treated with 2 N HCl in EA (0.5 mL).The reaction mixture was stirred at r.t. overnight and quenched withsat. NaHCO₃ aq. solution. The mixture was extracted with DCM (2 mL×2).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC on C18 column (30×250 mm, 10 m) using MeCN/H₂O (20% to 100%)to afford(3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(9.4 mg, 48.7% yield). LC-MS calc. for C₃₁H₃₉ClN₃O₅S [M+H]⁺:m/z=600.22/602.22; Found=599.9/601.7. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d,J=8.5 Hz, 1H), 7.32 (s, 1H), 7.15 (s, 1H), 7.10 (d, J=1.8 Hz, 1H), 6.93(d, J=8.1 Hz, 1H), 5.45 (dd, J=15.3, 8.8 Hz, 2H), 5.39-5.24 (m, 2H),4.13 (d, J=12.0 Hz, 1H), 4.01 (d, J=12.3 Hz, 1H), 3.87-3.65 (m, 2H),3.65-3.48 (m, 2H), 3.48-3.38 (m, 1H), 3.32 (d, J=14.6 Hz, 2H), 3.23 (s,1H), 3.13 (d, J=8.2 Hz, 1H), 3.03 (dd, J=15.2, 6.0 Hz, 2H), 2.87-2.68(m, 1H), 2.64 (s, 4H), 2.31 (d, J=3.4 Hz, 2H), 2.02 (d, J=13.6 Hz, 2H),1.97-1.53 (m, 3H), 1.53-1.22 (m, 2H), 1.16 (dd, J=6.0, 3.4 Hz, 2H).

Example 118(3R,6R,7R,8Z,12S,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 117 using tert-butyl(3R,6R,7R,8Z,12S,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylate(P1, Example 117, step 4) in Step 5. LC-MS calc. for C₃₁H₃₉ClN₃O₅S[M+H]⁺: m/z=600.22/602.22; Found: 600.9/602.1. ¹H NMR (400 MHz, CDCl₃) δ7.68 (d, J=8.5 Hz, 1H), 7.41 (dd, J=8.3, 1.7 Hz, 1H), 7.18 (dd, J=8.8,2.4 Hz, 2H), 7.08 (d, J=2.1 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 5.58 (d,J=5.1 Hz, 2H), 4.08 (s, 2H), 3.78-3.55 (m, 3H), 3.48-3.25 (m, 4H), 3.22(s, 2H), 3.07 (dd, J=15.2, 8.0 Hz, 1H), 2.85-2.65 (m, 2H), 2.65-2.50 (m,5H), 2.40-2.30 (m, 1H), 2.01 (d, J=14.6 Hz, 1H), 1.87 (ddd, J=32.6,16.9, 6.0 Hz, 4H), 1.65-1.49 (m, 2H), 1.49-1.34 (m, 3H).

Example 119(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

Step 1: 1-(allyl(tert-butoxycarbonyl)amino)cyclopropane-1-carboxylicacid

This compound was prepared using procedures analogous to those describedfor Example 116 Step 2-3 using ethyl1-(tert-butoxycarbonylamino)cyclopropanecarboxylate to replace ethyl1-(tert-butoxycarbonylamino)cyclobutanecarboxylate in Step 2.

Step 2:(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-5 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and1-(allyl(tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid inStep 3. LC-MS calc. for C₃₂H₃₉ClN₃O₅S [M+H]⁺: m/z=612.22/614.22; Found:611.9/614.2. ¹H NMR (600 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.46 (d,J=7.9 Hz, 1H), 7.31 (s, 1H), 7.18 (dd, J=8.5, 2.0 Hz, 1H), 7.08 (d,J=2.0 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 5.40 (d, J=4.0 Hz, 2H), 4.08 (dd,J=37.7, 12.1 Hz, 2H), 3.79-3.67 (m, 2H), 3.29 (dd, J=34.7, 13.2 Hz, 2H),3.20-3.07 (m, 5H), 3.04 (dd, J=15.2, 6.4 Hz, 1H), 2.84-2.63 (m, 3H),2.37 (s, 1H), 2.00 (d, J=13.3 Hz, 1H), 1.95-1.72 (m, 4H), 1.69-1.49 (m,4H), 1.44-1.35 (m, 2H), 1.17-1.11 (m, 1H), 1.08 (dd, J=12.8, 8.7 Hz,1H), 0.95 (tdd, J=15.5, 9.4, 6.0 Hz, 1H).

Example 120(3R,6R,7R,8E,22S)-6′-Chloro-7-methoxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(Example 116) and formaldehyde aqueous solution (37%). LC-MS calc. forC₃₄H₄₃ClN₃O₅S [M+H]⁺: m/z=640.25/642.25; Found: 640.0/642.2. ¹H NMR (600MHz, CDCl₃) δ 7.67 (d, J=8.5 Hz, 1H), 7.45 (d, J=16.9 Hz, 1H), 7.16 (d,J=7.7 Hz, 1H), 7.08 (t, J=4.6 Hz, 1H), 6.90 (s, 2H), 5.41 (dd, J=14.8,9.0 Hz, 1H), 4.07 (dd, J=33.9, 11.7 Hz, 2H), 3.71 (d, J=14.7 Hz, 1H),3.48 (s, 1H), 3.34 (d, J=15.0 Hz, 1H), 3.26 (s, 3H), 2.97 (dd, J=34.6,21.1 Hz, 1H), 2.85-2.66 (m, 2H), 2.49 (s, 1H), 2.42 (s, 3H), 2.29 (s,1H), 2.17 (s, 1H), 2.11-1.88 (m, 6H), 1.83 (d, J=8.0 Hz, 1H), 1.65 (s,9H), 1.40 (t, J=12.9 Hz, 1H), 0.95-0.73 (m, 1H).

Example 121(3R,6R,7R,8E,12R,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

Step 1: (2R)-2-[allyl(tert-butoxycarbonyl)amino]propanoic acid

This compound was prepared using procedures analogous to those describedfor Example 116 Step 2-3 using methyl(2R)-2-(tert-butoxycarbonylamino)propanoate to replace ethyl1-(tert-butoxycarbonylamino)cyclobutanecarboxylate in Step 2.

Step 2: tert-butyl(3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylateand tert-butyl(3R,6R,7R,8Z,12R,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylate

These two compounds were prepared using procedures analogous to thosedescribed for Example 117 Step 2-3 using(2R)-2-[allyl(tert-butoxycarbonyl)amino]propanoic acid to replace(2S)-2-[allyl(tert-butoxycarbonyl)amino]propanoic acid in Step 2. P1(the earlier eluted product) was assigned to the cis-isomer and P2 (theearlier eluted product) was assigned to the trans-isomer.

Step 3:(3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 117 Step 5 using tert-butyl(3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylate(P2). LC-MS calc. for C₃₁H₃₉ClN₃O₅S [M+H]⁺: m/z=600.22/602.22; Found:599.9/602.0. ¹H NMR (600 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H), 7.34 (d,J=8.3 Hz, 1H), 7.30 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.08 (s, 1H), 6.95(d, J=8.3 Hz, 1H), 5.42-5.26 (m, 2H), 4.12 (d, J=12.1 Hz, 1H), 4.04 (d,J=12.1 Hz, 1H), 3.77-3.63 (m, 3H), 3.31 (d, J=14.5 Hz, 1H), 3.16 (d,J=6.9 Hz, 1H), 3.12 (s, 3H), 3.03 (dd, J=15.1, 6.4 Hz, 3H), 2.85-2.71(m, 2H), 2.71-2.59 (m, 1H), 2.28 (td, J=14.0, 9.1 Hz, 1H), 2.00 (t,J=6.8 Hz, 2H), 1.94-1.69 (m, 7H), 1.64 (dd, J=19.0, 9.5 Hz, 2H), 1.40(d, J=7.0 Hz, 2H).

Example 122(3R,6R,7R,8Z,12R,22S)-6′-Chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 117 Step 5 using tert-butyl(3R,6R,7R,8Z,12R,22S)-6′-chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]-pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-11-carboxylate(P1, Example 121 Step 2). LC-MS calc. for C₃₁H₃₉ClN₃O₅S [M+H]⁺:m/z=600.22/602.22; Found: 599.9/602.0. ¹H NMR (600 MHz, CDCl₃) δ 7.68(d, J=8.5 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.17 (d, J=6.6 Hz, 2H), 7.08(d, J=1.7 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 5.53 (s, 2H), 4.11-4.03 (m,2H), 3.75 (d, J=9.6 Hz, 1H), 3.69 (d, J=14.5 Hz, 1H), 3.53 (d, J=14.6Hz, 1H), 3.33 (dd, J=42.0, 19.1 Hz, 4H), 3.21 (s, 3H), 3.06 (dd, J=14.8,7.7 Hz, 1H), 2.82-2.69 (m, 2H), 2.60-2.51 (m, 1H), 2.40-2.32 (m, 1H),2.01 (dd, J=15.3, 8.8 Hz, 1H), 1.86 (ddd, J=42.9, 24.7, 5.6 Hz, 5H),1.65-1.53 (m, 2H), 1.41 (t, J=9.9 Hz, 4H), 1.27 (d, J=18.2 Hz, 1H).

Example 123(3R,6R,7R,8E,12R,22S)-6′-Chloro-7-methoxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 121). LC-MS calc. for C₃₂H₄₁ClN₃O₅S [M+H]⁺: m/z=614.24/616.24;Found: 614.0/615.8. ¹H NMR (600 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H),7.50 (dd, J=8.4, 2.0 Hz, 1H), 7.18 (dd, J=8.5, 2.1 Hz, 1H), 7.08 (d,J=2.1 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 5.74-5.67 (m, 1H), 5.44 (dd,J=15.7, 8.7 Hz, 1H), 4.09 (dd, J=24.3, 12.1 Hz, 2H), 3.71 (d, J=14.6 Hz,1H), 3.50 (d, J=8.8 Hz, 1H), 3.44-3.37 (m, 1H), 3.35 (d, J=14.7 Hz, 1H),3.23 (d, J=15.4 Hz, 2H), 3.09-3.02 (m, 2H), 2.97 (dd, J=14.9, 7.3 Hz,1H), 2.87 (dd, J=14.9, 4.3 Hz, 1H), 2.81 (s, 1H), 2.80-2.72 (m, 2H),2.55-2.46 (m, 2H), 2.37 (d, J=10.0 Hz, 2H), 2.15 (dd, J=15.0, 7.4 Hz,1H), 2.06-1.89 (m, 4H), 1.83 (d, J=7.6 Hz, 2H), 1.72-1.36 (m, 2H),1.35-1.19 (m, 2H), 0.97-0.76 (m, 2H).

Example 124(3R,6R,7R,8Z,12R,22S)-6′-Chloro-7-methoxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7R,8Z,12R,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 122). LC-MS calc. for C₃₂H₄₁ClN₃O₅S [M+H]⁺: m/z=614.24/616.24;Found: 614.0/615.8. ¹H NMR (600 MHz, CDCl₃) δ 7.93 (d, J=7.9 Hz, 1H),7.70 (d, J=8.7 Hz, 2H), 7.45 (dd, J=15.8, 7.4 Hz, 2H), 7.35 (d, J=8.5Hz, 1H), 7.18 (dd, J=27.6, 9.5 Hz, 3H), 7.06 (dd, J=16.6, 8.7 Hz, 3H),6.97 (s, 2H), 6.77 (dd, J=28.8, 20.2 Hz, 4H), 6.61 (s, 1H), 6.05 (s,1H), 5.80-5.61 (m, 3H), 5.46 (s, 1H), 5.31 (dd, J=15.4, 8.3 Hz, 1H),5.19 (s, 1H), 5.07 (s, 2H), 4.29 (d, J=11.2 Hz, 2H), 4.06 (d, J=10.7 Hz,3H), 3.85-3.71 (m, 3H), 3.71-3.18 (m, 20H), 2.87 (ddt, J=92.3, 76.4,36.2 Hz, 20H), 2.47 (d, J=30.6 Hz, 4H), 2.23 (t, J=38.8 Hz, 10H),2.11-1.74 (m, 20H), 1.74-1.45 (m, 10H), 1.45-1.18 (m, 12H), 1.18-0.95(m, 10H), 0.89 (ddd, J=29.8, 15.5, 8.0 Hz, 4H).

Example 125(3R,6R,7R,8E,12S,22S)-6′-Chloro-7-methoxy-12-(methoxymethyl)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

Step 1: methyl (2S)-2-hydroxy-3-methoxy-propanoate

Mg(ClO₄)₂ (819 mg, 3.67 mmol) was added to methyl(2S)-oxirane-2-carboxylate (1.5 g, 14.69 mmol) in methanol (2 mL) understirring vigorously. The reaction mixture was heated to 80° C. for 20 h.After the reaction was completed (monitored by GC, GC: SM Rt=4.68 min,product Rt=6.0 min), the mixture was cooled to r.t., filtered andconcentrated under reduced pressure. The residue was re-dissolved inheptane, filtered again and concentrated to remove MeOH completely. Theresidue (1.97 g) was used for next step directly.

Step 2: methyl (2S)-2-allyloxy-3-methoxy-propanoate

Allyl bromide (3.55 g, 29 mmol) was added to methyl(2S)-2-hydroxy-3-methoxy-propanoate (1.97 g, 14 mmol) in tert-butylmethyl ether (40 mL) and followed by addition of silver(I) oxide (6.8 g,29 mmol) for 3 d. The reaction was filtered through a pad of Celite andthe filtrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column (20 g) usingEtOAc/Heptanes (2% to 30%) to afford methyl(2S)-2-allyloxy-3-methoxy-propanoate (810.9 mg, 31.7% yield).

Step 3: (2S)-2-allyloxy-3-methoxy-propanoic acid

This compound was prepared using procedures analogous to those describedfor Example 86 Step 2 using methyl (2S)-2-allyloxy-3-methoxy-propanoateand LiOH.

Step 3:(3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-(methoxymethyl)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamideand (2S)-2-allyloxy-3-methoxy-propanoic acid. LC-MS calc. forC₃₂H₄₀ClN₂O₇S [M+H]⁺: m/z=631.22/633.21; Found: 631.0/632.8. ¹H NMR (600MHz, CDCl₃) δ 7.67 (d, J=8.5 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.24 (s,1H), 7.18 (d, J=8.2 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.99 (d, J=8.2 Hz,1H), 5.46 (d, J=15.6 Hz, 1H), 5.39 (dd, J=15.6, 8.3 Hz, 1H), 4.51-4.43(m, 1H), 4.12 (dd, J=23.8, 11.9 Hz, 2H), 3.84-3.75 (m, 2H), 3.69 (d,J=13.8 Hz, 2H), 3.60 (dd, J=10.3, 5.6 Hz, 1H), 3.56-3.46 (m, 1H), 3.40(s, 3H), 3.35 (d, J=14.6 Hz, 1H), 3.23-3.13 (m, 2H), 3.11 (s, 3H),2.83-2.63 (m, 3H), 2.35-2.25 (m, 1H), 2.06-1.97 (m, 1H), 1.97-1.77 (m,4H), 1.77-1.66 (m, 1H), 1.63 (dt, J=18.8, 9.5 Hz, 2H), 1.45 (t, J=12.5Hz, 1H).

Example 126(3R,6R,7R,8E,12S,22S)-6′-Chloro-7-methoxy-12-cyclopropyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1 T (S)-2-(allyl(tert-butoxycarbonyl)amino)-2-cyclopropylaceticacid

To a suspension of(2S)-2-(tert-butoxycarbonylamino)-2-cyclopropyl-acetic acid (1500 mg,6.97 mmol) in THF (20 mL) was added sodium hydride (60% in oil) (351 mg,14.6 mmol) and the reaction mixture was stirred at r.t. for 20 min.Allyl bromide (927 mg, 7.67 mmol) was added drop-wise. After addition,the reaction was stirred at 50° C. overnight. The reaction was quenchedwith 10 mL saturated aqueous NH₄Cl and extracted with EtOAc (2×20 mL).The combined organic extracts were washed with water and brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withEtOAc/Hept (3% to 8%) to afford(2S)-2-[allyl(tert-butoxycarbonyl)amino]-2-cyclopropyl-acetic acid (840mg, 47% yield) as a colorless oil.

Step 2:(3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-cyclopropyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-5 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and(S)-2-(allyl(tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid in Step3. LC-MS calc. for C₃₃H₄₁ClN₃O₅S [M+H]⁺: m/z=626.24/628.23; Found:626.0/628.2. ¹H NMR (600 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H), 7.37 (dd,J=8.3, 2.1 Hz, 1H), 7.32 (s, 1H), 7.17 (dd, J=8.5, 2.3 Hz, 1H),7.11-7.06 (m, 1H), 6.97 (d, J=8.3 Hz, 1H), 5.39-5.32 (m, 1H), 5.28 (d,J=5.6 Hz, 1H), 4.14-4.01 (m, 2H), 3.71 (d, J=14.6 Hz, 1H), 3.69-3.59 (m,2H), 3.31 (d, J=14.6 Hz, 1H), 3.12 (s, 3H), 3.02 (dd, J=14.9, 6.7 Hz,2H), 2.88 (d, J=13.5 Hz, 1H), 2.83-2.70 (m, 2H), 2.65 (q, J=8.3 Hz, 1H),2.32-2.18 (m, 2H), 2.00 (d, J=13.5 Hz, 2H), 1.94-1.78 (m, 4H), 1.80-1.69(m, 2H), 1.64 (p, J=11.1, 10.4 Hz, 2H), 1.46-1.37 (m, 1H), 1.02 (d,J=7.2 Hz, 1H), 0.73-0.54 (m, 3H).

Example 127(3R,6R,7R,8E,12S,22S)-6′-Chloro-12-cyclopropyl-7-methoxy-11-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.0-3,6.0-19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7R,8E,12S,22S)-6′-chloro-12-cyclopropyl-7-methoxy-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.0˜3,6.0˜19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 126). LC-MS calc. for C₃₄H₄₂ClN₃O₅S [M+H]⁺: m/z=640.3/642.3;Found: 640.0/642.2. ¹H NMR (600 MHz, DMSO-d₆) δ 7.65 (d, J=8.5 Hz, 1H),7.26 (dd, J=8.5, 2.3 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H), 7.13 (dd, J=8.2,1.9 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.08 (dd,J=13.4, 6.9 Hz, 1H), 5.70-5.58 (m, 1H), 4.00 (s, 2H), 3.55 (t, J=12.7Hz, 2H), 3.33 (s, 6H), 3.19 (s, 3H), 3.04 (dd, J=15.2, 10.0 Hz, 1H),2.78 (s, 4H), 2.13-2.04 (m, 1H), 2.04-1.94 (m, 2H), 1.94-1.87 (m, 2H),1.84 (dq, J=10.2, 5.5, 4.7 Hz, 2H), 1.69 (p, J=10.2 Hz, 2H), 1.39 (q,J=6.9 Hz, 1H), 1.04 (ddt, J=13.4, 9.2, 4.5 Hz, 1H), 0.89-0.83 (m, 1H),0.70 (td, J=8.6, 7.5, 4.0 Hz, 1H), 0.60 (tt, J=8.8, 3.4 Hz, 1H),0.56-0.47 (m, 2H).

Example 128(3R,6R,7R,8E,12S,22S)-6′-Chloro-7-methoxy-12-isopropyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1: (S)-2-(allyl(tert-butoxycarbonyl)amino)-3-methyl-butanoic acid

This compound was prepared using procedures analogous to those describedfor Example 116 Step 2-3 using methyl(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate to replace ethyl1-(tert-butoxycarbonylamino)cyclobutanecarboxylate in Step 2.

Step 2:(3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-isopropyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-5 using(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 8) and (S)-2-(allyl(tert-butoxycarbonyl)amino)butanoicacid in Step 3. LC-MS calc. for C₃₃H₄₃ClN₃O₅S [M+H]⁺: m/z=628.25/630.25;Found: 628.1/629.8. ¹H NMR (600 MHz, CDCl₃) δ 7.68 (dd, J=8.6, 3.9 Hz,1H), 7.38 (s, 1H), 7.26 (s, 1H), 7.16 (d, J=9.6 Hz, 1H), 7.11-7.01 (m,1H), 6.91 (s, 1H), 5.58-5.17 (m, 2H), 4.19-3.92 (m, 2H), 3.77-3.60 (m,2H), 3.32 (d, J=14.6 Hz, 1H), 3.15 (d, J=25.0 Hz, 3H), 3.02 (dd, J=15.0,6.7 Hz, 1H), 2.94 (s, 1H), 2.86-2.69 (m, 2H), 2.65 (s, 1H), 2.23 (dd,J=18.4, 10.8 Hz, 1H), 2.11-1.95 (m, 2H), 1.95-1.69 (m, 4H), 1.62 (dq,J=28.8, 9.6 Hz, 2H), 1.45-1.35 (m, 1H), 1.35-1.21 (m, 3H), 1.09-0.97 (m,4H), 0.94 (d, J=6.9 Hz, 1H), 0.88 (t, J=6.9 Hz, 1H).

Example 129(3R,6R,7R,8E,12S,22S)-6′-Chloro-7-methoxy-11-methyl-12-isopropyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-isopropyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 128). LC-MS calc. for C₃₄H₄₅ClN₃O₅S [M+H]⁺: m/z=642.27/644.27;Found: 642.0/643.8. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J=8.5 Hz, 1H),7.52 (dd, J=8.4, 2.1 Hz, 1H), 7.28 (s, 1H), 7.20 (dd, J=8.5, 2.4 Hz,1H), 7.10 (d, J=2.3 Hz, 1H), 7.05-6.93 (m, 1H), 6.07-5.16 (m, 2H),4.28-3.97 (m, 2H), 3.82-3.68 (m, 1H), 3.53-3.26 (m, 4H), 3.20-2.91 (m,2H), 2.91-2.66 (m, 3H), 2.58-2.14 (m, 4H), 2.14-1.90 (m, 5H), 1.91-1.54(m, 5H), 1.54-1.37 (m, 3H), 1.32-1.20 (m, 6H).

Example 130(3R,6R,7R,8Z,21S)-6′-Chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,11,13-triazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-oneAnd Example 131(3R,6R,7R,8E,21S)-6′-chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,11,13-triazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-one

Step 1:I-allyl-3-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-urea

To a stirred solution of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(120.0 mg, 0.23 mmol, Intermediate 8) in MeCN (5 mL) was addedtriethylamine (0.19 mL, 1.39 mmol) followed by phenyl chloroformate(0.09 mL, 0.70 mmol). The resulting mixture was stirred at r.t. for 20min. LC-MS showed the consumption of starting material. Allylamine (0.35mL, 4.6 mmol) was added and the reaction was stirred at r.t. overnight.Water (10 mL) was added, and extracted with EtOAc (10 mL×3). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column (12 g) with EtOAc/Heptanes (20% to100%) to afford1-allyl-3-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-urea(127 mg, 91% yield) as a white solid. LC-MS calc. for C₃₁H₃₉ClN₃O₅S[M+H]⁺: m/z=600.2/602.2; Found: 599.9/602.0.

Step 2:(3R,6R,7R,8Z,21S)-6′-chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,11,13-triazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-oneand(3R,6R,7R,8E,21S)-6′-chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,11,13-triazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-one

To a stirred solution of1-allyl-3-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1R)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-urea(108.0 mg, 0.18 mmol) in DCE (180 mL) was bubbled with nitrogen for 20min. Then Hoveyda-Grubbs II (22.5 mg, 0.04 mmol) was added undernitrogen. The reaction was further bubbled with nitrogen for 10 min. Thereaction was stirred at 80° C. under nitrogen overnight. The reactionwas cooled to r.t. and bubbled with air for 30 min. to deactivate thecatalyst. The residue was purified by flash chromatography on a silicagel column (12 g) using EtOAc/Heptanes (20% to 100%). The desiredfractions were collected, concentrated and re-purified by prep-HPLC onC18 column (30×250 mm, 10 m) using MeCN/H₂O (20% to 100%) to afford twoproducts: P1 as a white solid (the earlier eluted product, 7.4 mg, 7.2%)and P2 as a white solid (the latter eluted product, 32.4 mg, 31% yield).

PIwas assigned to the cis-isomer Example 130(3R,6R,7R,8Z,21S)-6′-chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,11,13-triazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-one.LC-MS calc. for C₂₉H₃₅ClN₃O₅S [M+H]⁺: m/z=572.2/574.2; Found:572.0/573.8. HPLC (cis isomer): C18 column (4.6×150 mm, 5 m); flowrate=1 mL/min; mobile phase: 60% MeCN/H₂O (with 0.1% TFA) 1 min, 60% to95% 7 min, 95% 7 min; λ=220 nm. tR=6.7 min. ¹H NMR (600 MHz, DMSO-d₆) δ10.58 (s, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.29-7.24(m, 1H), 7.19 (dd, J=8.5, 2.7 Hz, 1H), 7.12-7.05 (m, 1H), 7.02-6.94 (m,2H), 5.76-5.71 (m, 1H), 5.42 (dd, J=15.9, 7.8 Hz, 1H), 4.22 (q, J=11.5,11.0 Hz, 1H), 4.14-3.96 (m, 3H), 3.67 (d, J=14.5 Hz, 1H), 3.54-3.47 (m,1H), 3.47-3.39 (m, 2H), 3.11 (s, 3H), 2.80 (dq, J=16.4, 6.6, 5.5 Hz,1H), 2.72 (ddt, J=16.6, 10.9, 4.9 Hz, 2H), 2.07-1.95 (m, 3H), 1.95-1.82(m, 4H), 1.73-1.59 (m, 2H), 1.46 (t, J=12.1 Hz, 2H).

P2 was assigned to the trans-isomer Example 131 and(3R,6R,7R,8E,21S)-6′-chloro-7-methoxy-14,14-dioxo-spiro[19-oxa-14-thia-1,11,13-triazatetracyclo[13.7.2.03,6.018,23]tetracosa-8,15,17,23-tetraene-21,1′-tetralin]-12-one.LC-MS calc. for C₂₉H₃₅ClN₃O₅S [M+H]⁺: m/z=572.2/574.2; Found:571.9/573.7. HPLC (trans isomer): C18 column (4.6×150 mm, 5 m); flowrate=1 mL/min; mobile phase: 60% MeCN/H₂O (with 0.1% TFA) 1 min, 60% to95% 7 min, 95% 7 min; λ=220 nm. tR=9.6 min. ¹H NMR (600 MHz, DMSO-d₆) δ10.54 (s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.27 (dd, J=8.5, 2.4 Hz, 1H),7.21-7.11 (m, 3H), 7.05 (d, J=8.3 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 5.66(dt, J=15.8, 3.9 Hz, 1H), 5.40 (ddt, J=15.7, 7.5, 1.9 Hz, 1H), 4.20 (d,J=12.2 Hz, 1H), 4.07 (d, J=12.1 Hz, 1H), 3.88-3.73 (m, 2H), 3.63 (d,J=14.5 Hz, 1H), 3.52 (dd, J=7.4, 5.1 Hz, 1H), 3.42-3.30 (m, 3H), 3.25(dd, J=14.9, 9.2 Hz, 1H), 3.11 (s, 3H), 2.85-2.77 (m, 1H), 2.73 (q,J=8.3 Hz, 1H), 2.22 (dq, J=8.8, 3.6 Hz, 1H), 2.03 (dt, J=13.5, 4.2 Hz,1H), 1.92-1.83 (m, 4H), 1.71-1.60 (m, 1H), 1.56-1.42 (m, 2H).

Example 132(3R,6R,7R,8E,12R,22S)-6′-Chloro-7-methoxy-11-ethyl-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 121) and acetaldehyde. LC-MS calc. for C₃₃H₄₃ClN₃O₅S [M+H]⁺:m/z=628.25/630.25; Found: 628.0/630.2. ¹H NMR (300 MHz, CDCl₃) δ 7.70(d, J=8.5 Hz, 1H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.19 (dd, J=8.5, 2.3Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.03 (s, 1H), 6.99 (d, J=8.4 Hz, 1H),5.84-5.68 (m, 1H), 5.48 (dd, J=15.4, 8.5 Hz, 1H), 4.10 (s, 2H),3.81-3.67 (m, 1H), 3.59 (d, J=14.6 Hz, 2H), 3.48-3.37 (m, 1H), 3.37-3.28(m, 2H), 3.26 (s, 3H), 3.23-3.13 (m, 1H), 3.05 (dd, J=15.2, 9.3 Hz, 1H),2.88 (d, J=5.5 Hz, 1H), 2.85-2.64 (m, 4H), 2.51 (d, J=4.0 Hz, 1H),2.30-2.14 (m, 1H), 1.90 (ddd, J=16.7, 13.7, 6.3 Hz, 4H), 1.74-1.53 (m,2H), 1.48-1.36 (m, 1H), 1.28 (d, J=7.0 Hz, 4H), 1.10 (t, J=7.1 Hz, 3H).

Example 133(3R,6R,7R,8E,12R,22S)-6′-Chloro-7-methoxy-11-acetyl-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

To a solution of(3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 87) (32.4 mg, 0.04 mmol) in DCM (0.50 mL) was added acetylchloride (10.0 μL, 0.14 mmol) at r.t. The mixture was stirred for 10min. and LC-MS indicated the reaction was completed. The mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC on C18 column (30×250 mm, 10 m) with MeCN/H₂O (20% to 100%)(w/0.1% TFA) to afford the title product (9.9 mg, 35% yield). LC-MScalc. for C₃₃H₄₁ClN₃O₆S [M+H]⁺: m/z=642.23/644.23; Found: 642.0/644.2.¹H NMR (300 MHz, CDCl₃) δ 9.62 (d, J=13.2 Hz, 1H), 7.69 (d, J=8.5 Hz,1H), 7.50 (d, J=8.3 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.19 (dd, J=8.5,2.2 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 5.44 (dd,J=15.3, 7.2 Hz, 1H), 5.20 (d, J=4.2 Hz, 1H), 5.00 (s, 1H), 4.14 (d,J=9.1 Hz, 2H), 3.84 (ddd, J=23.1, 15.6, 9.4 Hz, 3H), 3.66 (t, J=14.1 Hz,2H), 3.40-3.19 (m, 3H), 3.19-3.04 (m, 4H), 2.89-2.50 (m, 4H), 2.36 (d,J=5.5 Hz, 1H), 2.15 (d, J=20.1 Hz, 3H), 2.08-1.54 (m, 4H), 1.45 (t,J=11.1 Hz, 4H).

Example 134 Methyl(3R,6R,7R,8E,12R,22S)-6′-Chloro-7-methoxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 133 using(3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 121) and methyl chloroformate. LC-MS calc. for C₃₃H₄₁ClN₃O₇S[M+H]⁺: m/z=658.23/660.23; Found: 658.4/660.3. ¹H NMR (600 MHz, CDCl₃) δ7.68 (d, J=8.5 Hz, 1H), 7.49 (s, 1H), 7.29 (d, J=15.1 Hz, 1H), 7.17 (d,J=8.5 Hz, 1H), 7.08 (d, J=1.9 Hz, 1H), 6.99 (s, 1H), 5.48 (s, 1H), 4.57(s, 1H), 4.09 (dd, J=30.4, 11.9 Hz, 2H), 3.90-3.80 (m, 1H), 3.80-3.60(m, 6H), 3.25 (dd, J=27.0, 13.3 Hz, 2H), 3.19-3.09 (m, 2H), 3.07 (s,1H), 2.84-2.69 (m, 2H), 2.65 (s, 1H), 2.35 (d, J=21.3 Hz, 1H), 1.99 (d,J=11.0 Hz, 1H), 1.97-1.86 (m, 2H), 1.80 (ddd, J=19.4, 16.4, 9.7 Hz, 2H),1.64 (ddd, J=36.5, 19.0, 9.2 Hz, 5H), 1.45-1.36 (m, 3H), 1.35-1.28 (m,1H).

Example 135(3R,6R,7R,8E,12R,22S)-6′-Chloro-7-methoxy-12-methyl-11-methylsulfonyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 133 using(3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 121) and methanesulfonyl chloride. LC-MS calc. forC₃₂H₄₁ClN₃O₇S₂ [M+H]⁺: m/z=678.2/680.2; Found: 678.4/680.3.

Example 136(3R,6R,7S,8E,22S)-6′-Chloro-7-methoxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1:2-(allylamino)-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-propanamide

This compound was prepared using procedures analogous to those describedfor Example 43 Step 2 using(3R)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 7) and 3-allyl-4,4-dimethyl-oxazolidine-2,5-dione (Example43 Step 1). LC-MS calc. for C₃₄H₄₅ClN₃₀SS [M+H]⁺: m/z=642.28/644.28;Found: 642.9/644.8.

Step 2:(3R,6R,7S,8E,22S)-6′-chloro-7-methoxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 4 using2-(allylamino)-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-propanamide.LC-MS calc. for C₃₂H₄₁ClN₃O₅S [M+H]⁺: m/z=614.24/616.24; Found:614.8/616.7. ¹H NMR (600 MHz, DMSO-d₆) δ 7.60 (d, J=8.5 Hz, 1H), 7.22(dd, J=8.5, 2.3 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.16 (d, J=1.8 Hz, 1H),6.96 (s, 1H), 6.85 (d, J=8.2 Hz, 1H), 5.74 (s, 1H), 5.58 (dd, J=15.8,6.0 Hz, 1H), 4.08-3.85 (m, 3H), 3.48 (d, J=14.3 Hz, 2H), 3.38 (dd,J=14.6, 7.9 Hz, 1H), 3.29-3.24 (m, 2H), 3.20 (s, 3H), 3.15 (dt, J=14.5,5.0 Hz, 1H), 2.83-2.76 (m, 1H), 2.75-2.68 (m, 1H), 2.64-2.56 (m, 1H),2.41-2.29 (m, 1H), 2.01 (ddt, J=13.7, 9.0, 4.5 Hz, 2H), 1.91-1.77 (m,3H), 1.75-1.41 (m, 4H), 1.32 (s, 3H), 1.23 (s, 3H).

Example 137(3R,6R,7S,8E,22S)-6′-Chloro-7-methoxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7S,8E,22S)-6′-chloro-7-methoxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 136) and formaldehyde aqueous solution (37%). LC-MS calc. forC₃₃H₄₃ClN₃O₅S [M+H]⁺: m/z=628.25/630.25; Found: 628.7/630.5. ¹H NMR (600MHz, CDCl₃) δ 7.66 (d, J=8.5 Hz, 1H), 7.53-7.43 (m, 1H), 7.16 (dd,J=8.5, 2.3 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H),6.92-6.85 (m, 1H), 5.83 (s, 1H), 5.54 (dd, J=15.6, 5.3 Hz, 1H),5.45-5.19 (m, 1H), 4.07 (q, J=11.9 Hz, 2H), 3.71 (d, J=14.8 Hz, 1H),3.63 (d, J=5.1 Hz, 1H), 3.35 (s, 4H), 3.07 (dd, J=15.1, 10.3 Hz, 1H),2.78 (dqt, J=22.2, 10.8, 5.1 Hz, 5H), 2.28 (s, 3H), 2.22 (t, J=7.7 Hz,1H), 2.03-1.89 (m, 6H), 1.89-1.80 (m, 2H), 1.76 (q, J=8.9 Hz, 2H), 1.63(ddd, J=18.1, 11.7, 5.4 Hz, 2H), 1.49-1.39 (m, 2H).

Example 138(3R,6R,7R,8E,22S)-6′-Chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

Step 1:(3R,6R,7R,8E,22S)-6′-chloro-7-acetoxy-11-tert-butoxycarbonyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24˜]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 26 Step 3-4 using[(1R)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetate (Intermediate 6) and1-[allyl(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid (Example116 Step 3) in Step 3. LC-MS calc. for C₃₉H₄₉ClN₃O₈S [M+H]⁺:m/z=754.29/756.28; Found: 754.0/756.4.

Step 2:(3R,6R,7R,8E,22S)-6′-chloro-7-acetoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

(3R,6R,7R,8E,22S)-6′-chloro-7-acetoxy-11-tert-butoxycarbonyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(40 mg, 0.05 mmol) was stirred in 2 N HCl in EtOAc (3 mL) at r.t.overnight. The reaction was diluted with EtOAc, washed with saturatedaqueous NaHCO₃solution and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford(3R,6R,7R,8E,22S)-6′-chloro-7-acetoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(35 mg, 100% yield) which was used for the next step without furtherpurification. LC-MS calc. for C₃₄H₄₁ClN₃O₆S [M+H]⁺: m/z=654.23/656.23;Found 654.0/656.2.

Step 3:(3R,6R,7R,8E,22S)-6′-chloro-7-acetoxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

To a solution of(3R,6R,7R,8E,22S)-6′-chloro-7-acetoxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(35 mg, 0.05 mmol) in DCE (2 mL) was added two drops of formaldehydeaqueous solution (37% wt %, ca. 22 mg, 0.26 mmol HCHO). After 30 min.,sodium cyanoborohydride (16.8 mg, 0.27 mmol) was added in one portion,and stirred at r.t. for 4 h. The reaction was diluted with DCM andwater, and filtered through a pad of Celite. The organic layer waswashed with saturated aqueous NaHCO₃solution and brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by Prep-HPLC on C18 column (30×250 mm, 10 m) with 20 to100% ACN/H₂O (t_(R)=24 min) to afford(3R,6R,7R,8E,22S)-6′-chloro-7-acetoxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(14 mg, 39% yield) as a white product. LC-MS calc. for C₃₅H₄₃ClN₃O₆S[M+H]⁺: m/z=668.26/670.25; Found: 668.0/670.3.

Step 4:(3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one

To a solution of(3R,6R,7R,8E,22S)-6′-chloro-7-acetoxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(14.0 mg, 0.02 mmol) in MeOH (0.5 mL) and THF (0.2 mL) was added asolution of potassium carbonate (28.95 mg, 0.21 mmol) in water (0.5 mL)at r.t. After 16 h, LC-MS indicated the completion of reaction. Thereaction was extracted with DCM, washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford(3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(10 mg, 76% yield), which was sufficiently pure without furtherpurifications. LC-MS calc. for C₃₃H₄₁ClN₃O₅S [M+H]⁺: m/z=626.25/628.24;Found: 626.0/628.2. ¹H NMR (600 MHz, CDCl₃) δ 7.67 (d, J=8.5 Hz, 1H),7.51 (dd, J=8.4, 2.2 Hz, 1H), 7.17 (dd, J=8.5, 2.4 Hz, 1H), 7.08 (d,J=2.3 Hz, 1H), 6.98 (app d, J=8.3 Hz, 2H), 5.70 (app s, 1H), 5.64-5.55(m, 1H), 4.12 (d, J=12.2 Hz, 1H), 4.07 (d, J=12.1 Hz, 1H), 4.00 (t,J=7.8 Hz, 1H), 3.73 (d, J=14.7 Hz, 1H), 3.51 (app s, 1H), 3.33 (d,J=14.8 Hz, 1H), 3.05 (dd, J=15.2, 10.0 Hz, 1H), 2.90-2.64 (m, 4H), 2.49(s, 1H), 2.42 (s, 3H), 2.31-2.23 (m, 1H), 2.18-2.09 (m, 3H), 2.04-1.91(m, 5H), 1.88-1.78 (m, 1H), 1.75-1.60 (m, 3H), 1.49-1.39 (m, 1H).

Example 139[(3R,6R,7R,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34 using(3R,6R,7R,8E,22S)-6′-Chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(Example 138) and N,N-dimethylcarbamoyl chloride. LC-MS calc. forC₃₆H₄₆ClN₄O₆S [M+H]⁺: m/z=697.27/699.27; Found 697.9/699.7. ¹H NMR (600MHz, CDCl₃) δ 7.70 (d, J=8.5 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.18 (dd,J=8.5, 2.3 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 5.75(s, 1H), 5.57 (s, 1H), 5.38-5.31 (m, 1H), 5.01 (s, 1H), 4.12-4.02 (m,2H), 3.78 (d, J=14.5 Hz, 1H), 3.67 (s, 1H), 3.26 (d, J=14.6 Hz, 1H),3.02 (dd, J=15.2, 9.9 Hz, 2H), 2.92 (d, J=13.5 Hz, 5H), 2.80-2.71 (m,2H), 2.52 (s, 1H), 2.37 (s, 3H), 2.27 (s, 1H), 2.22 (t, J=7.7 Hz, 1H),2.15 (d, J=20.7 Hz, 1H), 2.07-1.98 (m, 4H), 1.98-1.90 (m, 3H), 1.90-1.76(m, 4H), 1.41 (t, J=12.7 Hz, 2H).

Example 1402-[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxy-N,N-dimethyl-acetamide

To a solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(20 mg, 0.03 mmol, Example 32) in THF (0.25 mL) was added NaH (5.3 mg,0.13 mmol, 60% suspension on mineral oil). The reaction was stirred at0° C. for 30 min., and 2-bromo-N,N-dimethyl-acetamide (33 mg, 0.20 mmol)was added. The reaction was slowly warmed to r.t. over 4 h. The reactionwas quenched with saturated NH₄Cl and diluted with EtOAc (3.0 mL). Theorganic layer separated, washed with water and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by Prep-HPLC on a C18 column with H₂O:MeCN (20% to 100%) toafford2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxy-N,N-dimethyl-acetamide(12 mg, 52% yield). LC-MS calc. for C₃₅H₄₅ClN₃O₇S [M+H]⁺:m/z=686.2/688.2; Found: 686.8/688.8.

Example 1412-[(3R,6R,7R,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxy-N,N-dimethyl-acetamide

This compound was prepared using procedures analogous to those describedfor Example 140 using(3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 36). LC-MS calc. for C₃₅H₄₅ClN₃O₇S [M+H]⁺: m/z=686.2/688.2;Found: 686.7/688.8.

Example 1422-[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-ethylene-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxy-N,N-dimethyl-acetamide

This compound was prepared using procedures analogous to those describedfor Example 140 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-ethylene-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 40). LC-MS calc. for C₃₅H₄₃ClN₃O₇S [M+H]⁺: m/z=684.2/686.2;Found: 684.7/686.9.

Example 1432-[(3R,6R,7R,8E,22S)-6′-Chloro-12,12-ethylene-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxy-N,N-dimethyl-acetamide

This compound was prepared using procedures analogous to those describedfor Example 140 using(3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-12,12-ethylene-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 38). LC-MS calc. for C₃₅H₄₃ClN₃O₇S [M+H]⁺: m/z=684.2/686.2;Found: 684.7/687.0.

Example 144(3R,6R,7S,8E,12R,22S)-6′-Chloro-7-hydroxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

Step 1:(3S)-5-[[(1R,2R)-2-[(S)-f-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a stirred solution of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide (300mg, 0.60 mmol, Intermediate 3) in DMF (5 mL) was added TBSCl (224 mg,1.49 mmol) and imidazole (203 mg, 2.98 mmol). The resulting solution wasstirred at 20° C. overnight. The reaction was quenched with water (15mL), and extracted with EtOAc (20 mL×3). The combined organic layerswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column (12 g) with EtOAc/Heptanes (2% to 75%) to afford(3S)-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(315 mg, 85% yield) as a white solid. LC-MS calc. for C₃₂H₄₆ClN₂₀₄SiS[M+H]⁺: m/z=617.3/619.3; Found 617.5/619.8.

Step 2: tert-butylN-allyl-N-[(1R)-2-[[(3S)-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-1-methyl-2-oxo-ethyl]carbamate

A solution of(3S)-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(315 mg, 0.51 mmol), (2R)-2-[allyl(tert-butoxycarbonyl)amino]propanoicacid (233 mg, 1.02 mmol, Example 121 Step 1) in DCM (3 mL) was addedDMAP (206 mg, 2.04 mmol) and EDCI (195 mg, 1.02 mmol) at r.t. Themixture was stirred for 3 h. The reaction was diluted with DCM (10 mL),washed with 1 N HCl (3 mL) and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure The residue was purified by flashchromatography on a silica gel column (12 g) with EtOAc/Heptanes (2% to50%) to afford tert-butylN-allyl-N-[(1R)-2-[[(3S)-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-1-methyl-2-oxo-ethyl]carbamate(264 mg, 62% yield) as a white solid. LC-MS calc. for C₄₃H₆₃ClN₃O₇SiS[M+H]⁺: m/z=828.4/830.4; Found 828.9/830.9.

Step 3: tert-butylN-allyl-N-[(1R)-2-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-1-methyl-2-oxo-ethyl]carbamate

To a stirred solution of tert-butylN-allyl-N-[(1R)-2-[[(3S)-5-[[(1R,2R)-2-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyallyl]cyclobutyl]methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-1-methyl-2-oxo-ethyl]carbamate(230 mg, 0.28 mmol) in THF (10 mL) was added TBAF (725 mg, 2.78 mmol, 1M in THF, pre-treated with molecular sieve). The resulting solution wasstirred at 20° C. overnight. The reaction was quenched with sat. NH₄Claq. Solution (10 mL), and extracted with EtOAc (20 mL×3). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon a silica gel column (12 g) with EtOAc/Heptanes (2% to 60%) to affordtert-butylN-allyl-N-[(1R)-2-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-1-methyl-2-oxo-ethyl]carbamate(190 mg, 95% yield). LC-MS calc. for C₃₇H₄₉ClN₃O₇S [M+H]⁺:m/z=714.3/716.3; Found 714.8/717.0.

Step 4: tert-butyl(3R,6R,7S,8E,12R,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylate

A solution of tert-butylN-allyl-N-[(1R)-2-[[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-1-methyl-2-oxo-ethyl]carbamate(260 mg, 0.36 mmol) in DCE (200 mL) was bubbled with N₂ for 30 min.1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]-methyleneruthenium(II)dichloride(Zhan-catalyst-1B) (53.42 mg, 0.07 mmol) was added and the reactionmixture was further bubbled with N₂ for 30 min, and was heated to 40° C.under N₂ for 3 h. LC-MS analysis indicated the completion of reaction.The reaction was cool to r.t. while being exposed to air. The reactionwas concentrated under reduced pressure, and the residue was purified byflash chromatography on a silica gel column (12 g) with EtOAc/Heptanes(2% to 50%) to afford two products: P1 (the earlier eluted product, 110mg, 44.0% yield) as a light brown colored solid and P2 (the lattereluted product, 90 mg, 0.13 mmol, 36% yield) as a light brown coloredsolid.

P1 was assigned to the trans-isomer tert-butyl(3R,6R,7S,8E,12R,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylate.LC-MS calc. for C₃₅H₄₅ClN₃O₇S [M+H]⁺: m/z=686.3/688.3; Found:686.8/688.3.

And P2 was assigned to the cis-isomer tert-butyl(3R,6R,7S,8Z,12R,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylate.LC-MS calc. for C₃₅H₄₅ClN₃O₇S [M+H]⁺: m/z=686.3/688.3; Found:686.8/688.3.

Step 5:(3R,6R,7S,8E,12R,22S)-6′-chloro-7-hydroxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

A solution of tert-butyl(3R,6R,7S,8E,12R,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylate(110.0 mg, 0.16 mmol, P1 from Step 4) in DCE (2 mL) was added phosphoricacid (3.0 mL, 51 mmol) and the resulting solution was stirred at 20° C.overnight. LC-MS analysis indicated the completion of reaction. Thereaction was quenched with aq. 1M NaOH solution (20 mL) and extractedwith DCM (10 mL×2). The combined organic layers were concentrated underreduced pressure to afford(3R,6R,7S,8E,12R,22S)-6′-chloro-7-hydroxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.0˜3,6.0˜19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(87 mg, 92% yield) as a light brown colored solid. LC-MS calc. forC₃₀H₃₇ClN₃O₅S [M+H]⁺: m/z=586.2/588.2; Found: 586.7/588.6.

Step 6:(3R,6R,7S,8E,12R,22S)-6′-chloro-7-hydroxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7S,8E,12R,22S)-6′-chloro-7-hydroxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-oneand formaldehyde aqueous solution (37%). LC-MS calc. for C₃₁H₃₉ClN₃O₅S[M+H]⁺: m/z=600.2/602.2; Found: 600.6/602.8. ¹H NMR (600 MHz, CDCl₃) δ7.69 (s, 1H), 7.01 (d, J=28.3 Hz, 2H), 6.69 (d, J=141.3 Hz, 2H), 6.20(s, 1H), 5.63 (d, J=15.5 Hz, 1H), 5.43-5.24 (m, 1H), 4.11 (s, 1H),4.05-3.69 (m, 3H), 3.59-3.46 (m, 1H), 3.25-3.06 (m, 2H), 2.79 (d, J=83.6Hz, 5H), 2.31 (s, 3H), 2.24-2.19 (m, 1H), 2.08-1.93 (m, 3H), 1.83 (s,3H), 1.59 (d, J=56.9 Hz, 4H), 1.44 (d, J=7.6 Hz, 2H).

Example 145[(3R,6R,7S,8E,12R,22S)-6′-Chloro-11,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34 using(3R,6R,7S,8E,12R,22S)-6′-chloro-7-hydroxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-oneand N,N-dimethylcarbamoyl chloride. LC-MS calc. for C₃₄H₄₄ClN₄O₆S[M+H]⁺: m/z=671.3/673.3; Found: 671.7/673.9. ¹H NMR (300 MHz, CDCl₃) δ7.65 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.5, 2.3 Hz,1H), 7.13-6.88 (m, 3H), 5.84-5.46 (m, 2H), 5.30 (d, J=4.3 Hz, 1H),4.32-3.97 (m, 3H), 3.67 (d, J=14.5 Hz, 2H), 3.42-3.28 (m, 2H), 2.95 (d,J=6.1 Hz, 6H), 2.79 (p, J=6.2, 4.7 Hz, 3H), 2.64 (s, 3H), 2.54-2.36 (m,2H), 2.16-1.73 (m, 7H), 1.68-1.48 (m, 3H), 1.35 (s, 3H).

Example 146[(3R,6R,7S,8E,12R,22S)-6′-Chloro-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

Step 1: tert-butyl(3R,6R,7S,8E,12R,22S)-6′-chloro-7-(dimethylcarbamoyloxy)-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.0˜3,6.0˜19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-

This compound was prepared using procedures analogous to those describedfor Example 34 using tert-butyl(3R,6R,7S,8E,12R,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylate(P1 Example 144 Step 4) and N,N-dimethylcarbamoyl chloride. LC-MS calc.for C₃₈H₅₀ClN₄O₈S [M+H]⁺: m/z=757.30/759.30; Found: 758.04/760.12.

Step 2:[(3R,6R,7S,8E,12R,22S)-6′-chloro-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.0˜3,6.0-19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 144 Step 5 using tert-butyl(3R,6R,7S,8E,12R,22S)-6′-chloro-7-(dimethylcarbamoyloxy)-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylateand phosphoric acid. LC-MS calc. for C₃₃H₄₂ClN₄O₆S [M+H]⁺:m/z=657.24/659.24; Found: 657.73/659.70. ¹H NMR (300 MHz, CDCl₃) δ 7.67(dd, J=8.6, 4.5 Hz, 1H), 7.43-7.33 (m, 1H), 7.29 (s, 1H), 7.20-7.06 (m,3H), 6.94 (dd, J=8.4, 4.6 Hz, 1H), 5.76-5.52 (m, 2H), 5.15 (t, J=4.6 Hz,1H), 4.23-3.97 (m, 2H), 3.63 (dd, J=14.5, 9.7 Hz, 2H), 3.54-3.25 (m,5H), 2.86 (s, 3H), 2.80-2.72 (m, 4H), 2.67-2.47 (m, 3H), 2.23 (t, J=7.4Hz, 2H), 2.02-1.75 (m, 6H), 1.47 (d, J=6.7 Hz, 4H).

Example 147[(3R,6R,7S,8E,12S,22S)-6′-Chloro-11,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

Step 1: tert-butyl(3R,6R,7S,8E,12S,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylateand tert-butyl(3R,6R,7S,8Z,12S,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylate

The compounds were prepared using procedures analogous to thosedescribed for Example 32 Step 1-3 using(3S)6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 3) and (2S)-2-[allyl(tert butoxycarbonyl)amino]propanoicacid (Example 85 Step 1) in Step 1. The reaction mixture was purified byflash chromatography on a silica gel column with EtOAc/Heptanes (3% to50%) to afford two products: P1 (the earlier eluted product) wasassigned to the Z-isomer tert-butyl(3R,6R,7S,8Z,12S,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylateand P2 (the latter eluted product) was assigned to the E-isomertert-butyl(3R,6R,7S,8E,12S,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylate.LC-MS calc. for C₃₅H₄₅ClN₃O₇S [M+H]⁺: m/z=686.2/688.2; Found:686.7/688.1.

Step 2:(3R,6R,7S,8E,12S,22S)-6′-chloro-7-hydroxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 144 Step 5 usingtert-butyl(3R,6R,7S,8E,12S,22S)-6′-chloro-7-hydroxy-12-methyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-11-carboxylate(P2 Step 1) and phosphoric acid (85% solution in water). LC-MS calc. forC₃₀H₃₇ClN₃₀SS [M+H]⁺: m/z=586.2/588.2; Found: 586.6/588.6.

Step 3:(3R,6R,7S,8E,12S,22S)-6′-chloro-7-hydroxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

The compounds were prepared using procedures analogous to thosedescribed for Example 27using(3R,6R,7S,8E,12S,22S)-6′-chloro-7-hydroxy-12-methyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-oneand formaldehyde aqueous solution (37%). LC-MS calc. for C₃₁H₃₉ClN₃O₅S[M+H]⁺: m/z=600.2/602.2; Found: 600.8/602.6.

Step 4:[(3R,6R,7S,8E,12S,22S)-6′-chloro-11,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

The compounds were prepared using procedures analogous to thosedescribed for Example 34 using(3R,6R,7S,8E,12S,22S)-6′-chloro-7-hydroxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-oneand N,N-dimethylcarbamoyl chloride. LC-MS calc. for C₃₄H₄₄ClN₄O₆S[M+H]⁺: m/z=671.26/673.26; Found: 671.7/673.8.

Example 148[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-(2 hydroxyethyl)piperazine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(2.8 g, 4.66 mmol, Example 32) in Step 1 and 2-piperazin-1-ylethanol inStep 2. LC-MS calc. for C₃₈H₅₀ClN₄O₈S [M+H]⁺: m/z=757.30/759.30; Found:757.7/759.7. ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H), 7.50 (dd,J=8.3, 2.0 Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (d, J=2.0 Hz,1H), 6.98 (dd, J=7.6, 5.2 Hz, 2H), 5.91-5.78 (m, 1H), 5.71 (dd, J=15.7,4.9 Hz, 1H), 5.33 (d, J=9.1 Hz, 1H), 4.12 (dt, J=13.9, 9.6 Hz, 4H),3.80-3.67 (m, 2H), 3.67-3.61 (m, 2H), 3.47 (d, J=4.4 Hz, 1H), 3.41 (s,1H), 3.37 (d, J=14.6 Hz, 1H), 3.21 (dd, J=15.0, 9.3 Hz, 2H), 2.87-2.67(m, 5H), 2.61-2.55 (m, 3H), 2.45-2.33 (m, 3H), 1.99 (dd, J=24.2, 8.9 Hz,4H), 1.89-1.72 (m, 4H), 1.64 (t, J=9.4 Hz, 2H), 1.50 (d, J=12.7 Hz, 1H),1.45 (s, 3H), 1.37 (s, 3H).

Example 149[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[2-(4-methylpiperazin-1-yl)ethyl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 2-(4-methylpiperazin-1-yl)ethanamine to replace1-(2-methoxyethyl)piperazine in Step 2. LC-MS calc. for C₃₉H₅₃ClN₅O₇S[M+H]⁺: m/z=770.34/772.34; Found: 770.7/772.7. ¹H NMVR (300 MHz, CDCl₃)δ 7.71 (d, J=8.5 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.19 (dd, J=8.5, 2.1Hz, 1H), 7.09 (s, 2H), 6.93 (d, J=8.3 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H),6.49 (s, 1H), 6.18 (d, J=15.2 Hz, 1H), 5.58 (d, J=15.6 Hz, 1H), 5.18 (s,1H), 4.20-4.02 (m, 4H), 3.66 (dd, J=34.7, 13.8 Hz, 3H), 3.30 (dd,J=17.0, 9.0 Hz, 2H), 3.01 (d, J=14.9 Hz, 5H), 2.80 (d, J=12.3 Hz, 7H),2.39 (s, 3H), 2.32-2.18 (m, 2H), 1.88 (ddd, J=27.1, 21.1, 12.4 Hz, 6H),1.59 (dd, J=18.3, 8.8 Hz, 3H), 1.39 (d, J=2.5 Hz, 6H).

Example 150[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[2-(4-hydroxy-1-piperidyl)ethyl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 1-(2-aminoethyl)piperidin-4-ol to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₉H₅₂ClN₄O₈S[M+H]⁺: m/z=771.32/773.32; Found: 771.8/773.8. 1H NMR (300 MHz, CDCl₃) δ7.73 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.18 (dd, J=8.4, 2.1 Hz,2H), 7.14-7.06 (m, 2H), 6.88 (d, J=8.2 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H),6.41-6.26 (m, 1H), 5.50 (d, J=15.8 Hz, 1H), 5.14 (s, 1H), 4.30 (dd,J=14.9, 4.9 Hz, 1H), 4.23-4.08 (m, 2H), 4.04 (d, J=12.6 Hz, 2H), 3.84(dd, J=15.6, 10.5 Hz, 2H), 3.77-3.63 (m, 3H), 3.30 (dd, J=39.0, 12.7 Hz,3H), 2.97 (dt, J=25.5, 13.4 Hz, 5H), 2.85-2.32 (m, 4H), 2.19 (dd,J=17.7, 8.8 Hz, 2H), 1.94 (dt, J=22.0, 14.6 Hz, 6H), 1.85-1.68 (m, 4H),1.67-1.48 (m, 3H), 1.37 (d, J=8.6 Hz, 6H).

Example 151[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[(3S)-1-methylpyrrolidin-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3S)-1-methylpyrrolidin-3-amine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₇H₄₈ClN₄O₇S[M+H]⁺: m/z=727.3/729.3; Found: 727.5/729.2. ¹H NMR (300 MHz, CDCl₃) δ7.71 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.3, 2.0 Hz, 1H), 7.17 (dd, J=8.5,2.2 Hz, 1H), 7.07 (dd, J=4.2, 2.2 Hz, 2H), 6.87 (d, J=8.2 Hz, 1H),6.42-6.12 (m, 1H), 5.47 (dd, J=15.8, 2.6 Hz, 1H), 5.08 (s, 1H),4.47-4.28 (m, 2H), 4.13-4.00 (m, 3H), 3.87 (d, J=11.6 Hz, 1H), 3.77-3.59(m, 2H), 3.21 (d, J=14.3 Hz, 1H), 3.07-2.85 (m, 6H), 2.80-2.66 (m, 7H),2.48 (ddd, J=14.3, 7.1, 3.1 Hz, 1H), 2.21-2.13 (m, 2H), 2.05-1.85 (m,3H), 1.77 (td, J=9.3, 8.9, 3.0 Hz, 2H), 1.59-1.48 (m, 1H), 1.36 (s, 3H),1.33 (s, 3H).

Example 152[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[(3R)-1-methylpyrrolidin-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3R)-1-methylpyrrolidin-3-amine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₇H₄₈ClN₄O₇S[M+H]⁺: m/z=727.3/729.3; Found: 727.6/729.3. ¹H NMR (300 MHz, CDCl₃) δ7.71 (d, J=8.4 Hz, 1H), 7.32 (dd, J=8.1, 2.1 Hz, 1H), 7.17 (dd, J=8.5,2.4 Hz, 1H), 7.11-7.03 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 6.27 (dd,J=14.3, 6.9 Hz, 1H), 5.63-5.38 (m, 1H), 5.06 (s, 1H), 4.31 (td, J=13.4,12.5, 5.2 Hz, 2H), 4.19-3.97 (m, 3H), 3.81-3.57 (m, 3H), 3.22 (d, J=14.4Hz, 1H), 3.03-2.33 (m, 17H), 2.18 (q, J=8.9, 7.3 Hz, 1H), 2.04-1.72 (m,5H), 1.54 (p, J=9.2 Hz, 1H), 1.37 (s, 3H), 1.34 (s, 3H).

Example 153[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[(3R)-1-methylpyrrolidin-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 3-hydroxyazetidine-1-carboxylate to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₅H₄₃ClN₃O₈S[M+H]⁺: m/z=700.24/702.24; Found: 700.3/702.0. ¹H NMR (300 MHz, CDCl₃) δ7.66 (d, J=8.5 Hz, 1H), 7.48-7.31 (m, 1H), 7.20-7.02 (m, 2H), 6.99-6.75(m, 2H), 6.26 (s, 1H), 5.64 (d, J=15.2 Hz, 1H), 5.09 (s, 1H), 4.55 (s,1H), 4.43-4.16 (m, 2H), 4.10-4.00 (m, 4H), 3.81 (d, J=12.8 Hz, 1H), 3.70(d, J=14.7 Hz, 1H), 3.62-3.44 (m, 1H), 3.41-3.34 (m, 2H), 3.01 (q, J=7.4Hz, 2H), 2.75 (d, J=10.5 Hz, 4H), 2.20 (q, J=7.3, 5.5 Hz, 1H), 1.99-1.75(m, 4H), 1.61 (q, J=9.3 Hz, 1H), 1.40-1.27 (m, 9H).

Example 154[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3S)-3-(dimethylamino)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3S)—N,N-dimethylpyrrolidin-3-amine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₅H₅₀ClN₄O₇S[M+H]⁺: m/z=741.3/743.3; Found: 741.4/743.2. ¹H NMR (499 MHz, DMSO-d₆) δ7.67 (dd, J=8.6, 3.4 Hz, 1H), 7.27 (dt, J=8.6, 2.0 Hz, 1H), 7.18 (d,J=2.4 Hz, 1H), 7.10 (dd, J=8.2, 2.0 Hz, 1H), 6.92-6.79 (m, 2H), 6.22 (s,1H), 5.71-5.21 (m, 2H), 5.10 (d, J=32.3 Hz, 1H), 4.02 (d, J=5.9 Hz, 2H),3.87 (d, J=9.4 Hz, 1H), 3.57 (d, J=13.5 Hz, 6H), 3.13-2.99 (m, 2H),2.86-2.64 (m, 4H), 2.29 (d, J=35.6 Hz, 5H), 2.13-1.91 (m, 4H), 1.86 (d,J=7.5 Hz, 4H), 1.67 (dd, J=21.5, 12.4 Hz, 3H), 1.45 (q, J=12.9, 10.8 Hz,2H), 1.22 (s, 3H), 1.12 (s, 3H).

Example 155[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[2-(dimethylamino)ethyl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using N′,N′-dimethylethane-1,2-diamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₆H₄₈ClN₄O₇S[M+H]⁺: m/z=715.29/717.29; Found: 715.4/717.2. 1H NMR (499 MHz, DMSO-d₆)δ 7.67 (d, J=8.6 Hz, 1H), 7.28 (dd, J=8.5, 2.4 Hz, 1H), 7.18 (d, J=2.4Hz, 1H), 7.15-7.00 (m, 2H), 6.95 (d, J=2.1 Hz, 1H), 6.85 (d, J=8.1 Hz,1H), 6.28 (s, 1H), 5.48 (dd, J=16.1, 3.7 Hz, 1H), 4.92 (s, 1H),4.10-3.95 (m, 2H), 3.89 (dd, J=14.0, 7.7 Hz, 1H), 3.77 (s, 1H), 3.55 (d,J=14.2 Hz, 2H), 3.27-3.12 (m, 4H), 3.12-3.00 (m, 2H), 2.86-2.56 (m, 7H),2.44-2.24 (m, 2H), 2.15-1.90 (m, 2H), 1.84 (dd, J=14.0, 7.6 Hz, 3H),1.67 (ddd, J=43.0, 21.1, 12.2 Hz, 3H), 1.45 (dt, J=26.0, 9.4 Hz, 2H),1.21 (s, 3H), 1.13 (s, 3H).

Example 156[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-(methylamino)azetidine-1-carboxylate

Step 1:[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-[tert-butoxycarbonyl(methyl)amino]azetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate toreplace 1-(2-methoxyethyl)piperazine in Step 2. The reaction mixture wasconcentrated under reduced pressure and the residue was directly usedfor the next step. LC-MS: calcd. for C₄₁H₅₄ClN₄₀₉S [M+H]⁺:m/z=813.3/815.3; Found: 813.7/815.5.

Step 2:[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7yl]3-(methylamino)azetidine-1-carboxylate

To a solution of[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.0-3,6.0˜-19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-[tert-butoxycarbonyl(methyl)amino]azetidine-1-carboxylate (30.0 mg,0.04 mmol) in IPA (1 mL) and DCM (0.10 mL) was added phosphoric acid(0.5 mL, 8.6 mmol). The resulting solution was vigorously stirred at 20°C. for 3 h. The reaction mixture was quenched with 1M NaOH aqueoussolution and extracted with DCM (2×2 mL). The combined organic layerswere concentrated under reduced pressure. The residue was purified byprep-HPLC on C18 column (30×250 mm, 10 m) with MeOH/H₂O (15% to 100%) toafford[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-(methylamino)azetidine-1-carboxylate (16.8 mg, 63.9% yield) as a whitesolid. LCMS calc. for C₃₆H₄₆ClN₄O₇S [M+H]⁺: m/z=713.28/715.28; Found:713.4/715.3. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.53-7.37(m, 1H), 7.22-7.05 (m, 3H), 7.00-6.78 (m, 2H), 5.67 (dd, J=15.9, 4.2 Hz,1H), 5.11 (s, 1H), 4.32-4.00 (m, 6H), 3.85-3.66 (m, 3H), 3.59 (s, 2H),3.39 (t, J=17.0 Hz, 3H), 3.22-3.07 (m, 3H), 2.79 (s, 3H), 2.56-2.35 (m,3H), 2.23 (t, J=7.6 Hz, 1H), 2.09-1.72 (m, 6H), 1.45 (s, 3H), 1.33 (s,3H).

Example 157[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[2-(methylamino)ethyl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 156 using tert-butyl N-(2-aminoethyl)-N-methyl-carbamate toreplace 4-amino-1-boc-piperidine in Step 1. LCMS calc. for C₃₅H₄₆ClN₄O₇S[M+H]⁺: m/z=701.28/703.28; Found 701.4/703.3. ¹H NMR (499 MHz, DMSO-d₆)δ 7.65 (dd, J=8.8, 4.1 Hz, 1H), 7.27 (dd, J=8.5, 2.4 Hz, 1H), 7.17 (d,J=2.2 Hz, 1H), 7.06 (dd, J=8.2, 1.9 Hz, 1H), 7.02-6.87 (m, 2H), 6.84 (d,J=8.1 Hz, 1H), 6.55-6.15 (m, 1H), 5.65-4.77 (m, 2H), 4.00 (s, 2H), 3.89(d, J=6.0 Hz, 2H), 3.66-3.50 (m, 2H), 3.19 (dd, J=24.7, 13.1 Hz, 3H),3.11-2.93 (m, 3H), 2.80 (d, J=18.4 Hz, 2H), 2.76-2.59 (m, 4H), 2.29 (d,J=8.7 Hz, 1H), 2.00 (ddd, J=21.8, 12.3, 6.1 Hz, 2H), 1.90-1.76 (m, 3H),1.76-1.56 (m, 3H), 1.49-1.34 (m, 2H), 1.23-1.18 (m, 3H), 1.12 (s, 3H).

Example 185[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]2,2-dimethylmorpholine-4-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 2,2-dimethylmorpholine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₇H₄₅ClN₃O₈S[M+H]⁺: m/z=742.29/744.29; Found: 742.6/744.6. 1H NMR (499 MHz, DMSO-d₆)δ 7.64 (d, J=8.6 Hz, 1H), 7.25 (ddd, J=8.5, 6.1, 2.3 Hz, 2H), 7.18 (d,J=2.4 Hz, 1H), 7.06-6.92 (m, 2H), 6.51 (s, 1H), 5.67 (s, 1H), 5.33 (td,J=4.5, 2.2 Hz, 1H), 5.18 (s, 1H), 4.18-4.03 (m, 3H), 4.01-3.86 (m, 1H),3.64-3.49 (m, 4H), 3.31-3.15 (m, 2H), 2.83-2.62 (m, 3H), 2.41-2.14 (m,1H), 2.05-1.94 (m, 4H), 1.83 (d, J=4.7 Hz, 3H), 1.68 (ddt, J=44.8, 18.3,8.4 Hz, 3H), 1.55-1.43 (m, 3H), 1.39 (s, 2H), 1.22 (s, 3H), 1,14-1.07(m, 5H).

Example 159[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-(2-methoxyethyl)-N-methyl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 2-methoxy-N-methyl-ethanamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₆H₄₇ClN₃O₈S[M+H]⁺: m/z=716.27/718.27; Found: 716.6/718.6. ¹H NMR (499 MHz, DMSO-d₆)δ 7.69-7.62 (m, 1H), 7.33-7.23 (m, 2H), 7.20 (dd, J=5.6, 2.4 Hz, 2H),6.94 (s, 2H), 5.73 (d, J=39.4 Hz, 1H), 5.39-5.05 (m, 1H), 4.23-3.83 (m,3H), 3.66-3.52 (m, 2H), 3.46 (s, 3H), 3.25 (d, J=12.2 Hz, 4H), 3.16-3.07(m, 1H), 2.97 (d, J=21.7 Hz, 1H), 2.91-2.63 (m, 5H), 2.60 (s, 1H),2.47-2.20 (m, 2H), 2.01 (dt, J=18.3, 7.8 Hz, 3H), 1.86 (s, 3H),1.78-1.59 (m, 3H), 1.57-1.42 (m, 2H), 1.42-1.33 (m, 2H), 1.20-1.12 (m,2H).

Example 160[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](2S)-2-(methoxymethyl)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (2S)-2-(methoxymethyl)pyrrolidine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₈H₄₉ClN₃O₈S[M+H]⁺: m/z=742.29/744.28; Found: 742.5/744.5. ¹H NMR (499 MHz, DMSO-d₆)δ 7.64 (d, J=8.5 Hz, 1H), 7.28-7.21 (m, 2H), 7.19-7.16 (m, 1H), 7.02 (d,J=8.3 Hz, 1H), 6.98-6.94 (m, 1H), 6.65 (s, 1H), 5.72-5.67 (m, 1H),5.21-5.15 (m, 1H), 4.09 (t, J=15.3 Hz, 2H), 3.94 (d, J=15.4 Hz, 1H),3.86-3.83 (m, 1H), 3.56 (d, J=14.9 Hz, 1H), 3.28-3.15 (m, 7H), 2.80-2.72(m, 2H), 2.04-1.94 (m, 5H), 1.83-1.77 (m, 6H), 1.49-1.46 (m, 2H),1.42-1.38 (m, 2H), 1.28-1.22 (m, 10H).

Example 161[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](2R)-2-(methoxymethyl)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (2R)-2-(methoxymethyl)pyrrolidine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₈H₄₉ClN₃O₈S[M+H]⁺: m/z=742.29/744.28; Found: 742.5/744.5.

Example 162[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3S)-3-ethoxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3S)-3-ethoxypyrrolidine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₈₃H₄₉ClN₃O₈S[M+H]⁺: m/z=742.29/744.28; Found: 742.6/744.6. ¹H NMR (300 MHz, CDCl₃) δ7.69 (d, J=8.5 Hz, 1H), 7.34 (t, J=7.2 Hz, 1H), 7.13 (dt, J=8.6, 2.2 Hz,1H), 7.06 (d, J=2.2 Hz, 1H), 6.99 (s, 1H), 6.84 (dd, J=8.3, 4.0 Hz, 1H),6.13 (s, 1H), 5.70 (dt, J=14.7, 6.4 Hz, 1H), 5.17 (d, J=4.6 Hz, 1H),4.08-3.93 (m, 4H), 3.84 (d, J=13.0 Hz, 1H), 3.67 (d, J=14.4 Hz, 1H),3.50-3.42 (m, 7H), 3.25 (d, J=14.3 Hz, 1H), 3.15-3.01 (m, 1H), 2.75 (q,J=5.2 Hz, 2H), 2.37-2.30 (m, 1H), 2.21 (t, J=7.6 Hz, 1H), 2.02-1.86 (m,5H), 1.81-1.75 (m, 3H), 1.62-1.54 (m, 1H), 1.34-1.15 (m, 11H).

Example 163[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3S)-3-(methylamino)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 156 using tert-butylN-methyl-N-[(3S)-pyrrolidin-3-yl]carbamate to replace4-amino-1-boc-piperidine in Step 1. LCMS calc. for C₃₇H₄₈ClN₄O₇S [M+H]⁺:m/z=727.3/729.3; Found: 727.5/729.3. ¹H NMR (300 MHz, CDCl₃) δ 7.70 (d,J=8.5 Hz, 1H), 7.40 (dd, J=8.3, 2.0 Hz, 1H), 7.16 (dd, J=8.5, 2.3 Hz,1H), 7.06 (d, J=2.3 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.81 (d, J=2.2 Hz,1H), 6.29 (td, J=10.4, 9.0, 4.9 Hz, 1H), 5.64 (dt, J=15.9, 2.7 Hz, 1H),5.09 (s, 1H), 4.36 (d, J=12.4 Hz, 1H), 4.17-3.97 (m, 3H), 3.84 (d,J=13.4 Hz, 1H), 3.76-3.07 (m, 14H), 2.98-2.89 (m, 1H), 2.78 (d, J=8.6Hz, 3H), 2.34-2.11 (m, 3H), 1.92-1.85 (m, 5H), 1.61 (d, J=6.6 Hz, 1H),1.38 (s, 3H), 1.32 (s, 3H).

Example 164[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-(methylamino)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 156 using tert-butylN-methyl-N-[(3R)-pyrrolidin-3-yl]carbamate to replace4-amino-1-boc-piperidine in Step 1. LCMS calc. for C₃₇H₄₈ClN₄O₇S [M+H]⁺:m/z=727.3/729.3; Found: 727.3/729.1. ¹H NMR (499 MHz, DMSO-d₆) δ 7.65(d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5, 2.4 Hz, 1H), 7.20-7.13 (m, 1H),7.10-6.99 (m, 1H), 6.91-6.73 (m, 2H), 6.22-6.17 (m, 1H), 5.54-5.46 (m,1H), 4.91 (s, 1H), 4.11-3.94 (m, 3H), 3.90-3.78 (m, 2H), 3.70-3.65 (m,4H), 3.01 (dd, J=16.0, 10.5 Hz, 2H), 2.88-2.67 (m, 4H), 2.67-2.55 (m,3H), 2.29 (dq, J=15.3, 7.5, 6.3 Hz, 1H), 2.22-2.07 (m, 2H), 2.03-1.92(m, 2H), 1.89-1.81 (m, 3H), 1.70-1.63 (m, 3H), 1.47-1.34 (m, 1H), 1.24(s, 3H), 1.18 (s, 3H), 1.08 (d, J=8.4 Hz, 2H) ppm.

Example 165[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-fluoroazetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 3-Fluoroazetidine hydrochloride and Hunig's Base toreplace 1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. forC₃₅H₄₂ClFN₃O₇S [M+H]⁺: m/z=702.23/704.23; Found: 702.7/704.7. ¹H NMR(300 MHz, CDCl₃) δ 9.13 (s, 1H, NH), 7.69 (d, J=8.5 Hz, 1H), 7.51 (dd,J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (d, J=2.1 Hz,1H), 7.02-6.98 (m, 1H), 6.96 (d, J=1.8 Hz, 1H), 5.88-5.79 (m, 1H), 5.70(dd, J=15.6, 4.9 Hz, 1H), 5.38 (m, 1H), 5.23 (m, 2H), 4.14 (m, 4H), 3.74(dd, J=14.1, 8.3 Hz, 2H), 3.37 (d, J=14.5 Hz, 2H), 3.22 (dd, J=15.0, 9.3Hz, 1H), 2.79 (d, J=4.1 Hz, 3H), 2.41-2.33 (m, 1H), 2.16 (s, 4H), 2.01(dd, J=16.7, 9.0 Hz, 3H), 1.83 (d, J=8.4 Hz, 2H), 1.64 (dt, J=18.8, 9.3Hz, 2H), 1.46 (s, 3H), 1.37 (s, 3H).

Example 166[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3,3-difluoropyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 3,3-Difluoropyrrolidine hydrochloride and Hunig'sbase to replace 1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. forC₃₆H₄₃ClF₂N₃O₇S [M+H]⁺: m/z=734.24/736.24; Found: 734.7/735.7. ¹H NMR(600 MHz, DMSO-d₆) δ 7.64 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.3 Hz, 2H),7.18 (s, 1H), 7.05-6.99 (m, 1H), 6.91 (s, 1H), 6.69-6.48 (m, 1H),5.92-5.62 (m, 2H), 4.15-3.98 (m, 4H), 3.81 (m, 2H), 2.80 (d, J=16.8 Hz,2H), 2.75-2.64 (m, 6H), 2.44 (s, 2H), 2.06-1.93 (m, 3H), 1.84 (d, J=4.0Hz, 2H), 1.72 (s, 1H), 1.65 (s, 2H), 1.52-1.44 (m, 2H), 1.38 (s, 3H),1.22 (s, 3H).

Example 167[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methoxycarbamate

To a solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(30.0 mg, 0.10 mmol, Example 32) in MeCN (3 mL) was added1,1′-carbonyldiimidazole (24.23 mg, 0.30 mmol). The mixture was stirredat 45° C. for 3 h. LCMS showed that the starting material was consumed.The mixture was concentrated, and the residue was re-dissolved in MeCN(1 mL) and water (1 mL). To the solution was added methoxyamine whichwas in-situ generated from methoxyamine hydrochloride (10.15 mg, 0.22mmol) by treatment with 2 drops of 2N NaOH solution. The mixture wasstirred at 45° C. overnight. The mixture was cooled down to r.t., 2drops of 2 N HCl in EA was added and concentrated under reducedpressure. The residue was purified by prep-HPLC on a C18 column usingH₂O/ACN (20-100%) to afford the desired product[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methoxycarbamate(7.8 mg, 26.8% yield). LCMS calc. for C₃₃H₄₁ClN₃O₈S [M+H]⁺:m/z=674.22/675.23; Found: 674.3/674.2; ¹H NMR (300 MHz, CDCl₃) δ 9.13(s, 1H, NH), 7.68 (d, J=8.5 Hz, 1H), 7.52 (dt, J=8.5, 2.5 Hz, 1H), 7.19(d, J=8.5 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.07-6.97 (m, 2H), 5.78 (t,J=5.8 Hz, 1H), 4.15 (m, 3H), 4.02-3.83 (m, 2H), 3.75 (d, J=8.2 Hz, 2H),3.50-3.23 (m, 3H), 2.88-2.70 (m, 3H), 2.45-2.33 (m, 1H), 2.10-1.95 (m,3H), 1.91 (dd, J=12.9, 6.4 Hz, 2H), 1.87-1.80 (m, 3H), 1.69-1.59 (m,2H), 1.58-1.49 (m, 2H), 1.44 (d, J=3.4 Hz, 3H), 1.38 (d, J=6.2 Hz, 3H).

Example 168[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](2S)-2-[(dimethylamino)methyl]pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using N,N-dimethyl-1-[(2S)-pyrrolidin-2-yl]methanamine toreplace 1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. forC₃₉H₅₂ClN₄O₇S [M+H]⁺: m/z=755.32/757.31; Found: 755.5/757.4. ¹H NMR (600MHz, DMSO-d₆) δ 9.11 (s, 1H, NH), 7.70 (d, J=8.6 Hz, 1H), 7.32 (td,J=8.0, 2.1 Hz, 2H), 7.25 (d, J=2.2 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 7.01(d, J=19.4 Hz, 1H), 5.75 (s, 2H), 5.24 (s, 1H), 4.17 (dd, J=27.1, 12.1Hz, 3H), 3.99 (d, J=13.3 Hz, 1H), 3.59 (m, 3H), 3.36-3.22 (m, 5H), 3.15(s, 1H), 2.92 (s, 3H), 2.87 (s, 3H), 2.85-2.71 (m, 4H), 2.05 (dt,J=12.0, 7.2 Hz, 2H), 1.93 (m, 4H), 1.80 (dd, J=24.4, 7.6 Hz, 2H), 1.69(m, 2H), 1.62-1.49 (m, 2H), 1.43 (s, 3H), 1.28 (s, 3H).

Example 169[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](2R)-2-[(dimethylamino)methyl]pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using N,N-dimethyl-1-[(2R)-pyrrolidin-2-yl]methanamine toreplace 1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. forC₃₉H₅₂ClN₄O₇S [M+H]⁺: m/z=755.32/757.31; Found: 755.6/757.5. ¹H NMR (600MHz, DMSO-d₆) δ 9.14 (s, 1H, NH), 7.65 (d, J=8.5 Hz, 1H), 7.26 (d, J=8.4Hz, 2H), 7.19 (d, J=1.5 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.92 (s, 1H),5.84-5.66 (m, 2H), 5.12 (s, 1H), 4.10 (dd, J=23.8, 12.3 Hz, 3H), 3.96(dt, J=28.1, 14.1 Hz, 1H), 3.62-3.53 (m, 2H), 3.32-3.20 (m, 6H),3.14-3.10 (m, 1H), 2.88 (t, J=8.8 Hz, 3H), 2.86-2.82 (m, 3H), 2.80 (dd,J=12.3, 4.1 Hz, 2H), 2.76-2.69 (m, 2H), 2.05-1.96 (m, 2H), 1.86 (m, 6H),1.76-1.69 (m, 2H), 1.65 (dd, J=18.7, 9.5 Hz, 1H), 1.52-1.46 (m, 1H),1.38 (d, J=8.7 Hz, 3H), 1.23 (s, 3H).

Example 170[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octanehydrochloride and N,N-diisopropylethylaamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₈H₄₇ClN₃O₈S[M+H]⁺: m/z=740.27/742.27; Found: 740.5/742.3. ¹H NMR (600 MHz, DMSO-d₆)δ 7.63 (t, J=8.3 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.19 (s, 1H), 6.98 (m,2H), 6.60 (d, J=77.3 Hz, 1H), 5.84-5.51 (m, 2H), 4.26 (m, 2H), 4.09 (dd,J=38.2, 12.5 Hz, 2H), 4.03-3.85 (m, 1H), 3.71-3.46 (m, 4H), 3.25 (s,3H), 3.06-2.96 (m, 1H), 2.80 (d, J=16.6 Hz, 1H), 2.76-2.64 (m, 2H),2.05-1.94 (m, 3H), 1.83 (s, 3H), 1.75 (t, J=20.1 Hz, 2H), 1.68-1.57 (m,4H), 1.52-1.44 (m, 2H), 1.24 (s, 6H).

Example 171[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15λ6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using(9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine;dihydrochloride and diisopropylethylamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₉H₅₀ClN₄O₈S[M+H]⁺: m/z=769.3/771.3; Found 769.5/771.5. ¹H NMR (300 MHz, CDCl₃) δ7.69 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.4, 2.2 Hz, 1H), 7.18 (d, J=8.5 Hz,1H), 7.09 (d, J=2.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 5.90-5.62 (m, 2H),5.43-5.27 (m, 1H), 4.16-4.00 (m, 4H), 3.95-3.63 (m, 6H), 3.40 (dd,J=22.9, 15.5 Hz, 2H), 3.21 (dd, J=15.4, 9.0 Hz, 2H), 3.06 (t, J=12.7 Hz,1H), 2.84-2.62 (m, 6H), 2.38 (qd, J=8.9, 3.4 Hz, 2H), 2.25 (q, J=9.2,7.1 Hz, 2H), 1.99 (tdd, J=14.5, 11.1, 6.4 Hz, 3H), 1.89-1.78 (m, 3H),1.65 (q, J=9.1 Hz, 2H), 1.44 (s, 3H), 1.37 (s, 3H).

Example 172[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]morpholine-4-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using morpholine to replace 1-(2-methoxyethyl)piperazinein Step 2. LCMS calc. for C₃₆H₄₅ClN₃O₈S [M+H]⁺: m/z=714.26/716.26;Found: 714.7/716.7. ¹H NMR (600 MHz, CDCl₃) δ 9.03 (s, 1H), 7.67 (d,J=8.5 Hz, 1H), 7.49 (dd, J=8.3, 2.1 Hz, 1H), 7.18 (dd, J=8.5, 2.2 Hz,1H), 7.09 (d, J=2.0 Hz, 1H), 6.97 (dd, J=17.3, 5.2 Hz, 2H), 5.91-5.63(m, 2H), 5.35 (s, 1H), 4.27-4.03 (m, 3H), 3.87-3.11 (m, 12H), 2.77 (dd,J=11.1, 5.2 Hz, 3H), 2.39 (dd, J=8.7, 3.3 Hz, 1H), 2.09-1.91 (m, 3H),1.81 (ddd, J=29.9, 18.4, 9.7 Hz, 3H), 1.70-1.58 (m, 3H), 1.44 (s, 3H),1.36 (s, 3H).

Example 173[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using pyrrolidine to replace 1-(2-methoxyethyl)piperazinein Step 2. LCMS calc. for C₃₆H₄₅ClN₃O₇S [M+H]⁺: m/z=698.26/700.26;Found: 698.4/700.4. ¹H NMR (500 MHz, CDCl₃) δ 9.07 (s, 1H), 7.67 (d,J=8.5 Hz, 1H), 7.52-7.44 (m, 1H), 7.17 (dd, J=8.5, 2.3 Hz, 1H), 7.08 (d,J=2.3 Hz, 1H), 6.98 (dd, J=5.3, 3.0 Hz, 2H), 5.77 (ddd, J=20.5, 16.0,8.3 Hz, 2H), 5.37-5.33 (m, 2H), 5.30 (s, 1H), 4.07 (dd, J=13.7, 5.9 Hz,1H), 3.84-3.65 (m, 2H), 3.51-3.44 (m, 2H), 3.37 (d, J=14.9 Hz, 2H), 3.21(dd, J=14.9, 9.3 Hz, 1H), 2.85-2.71 (m, 3H), 2.36 (dd, J=9.0, 3.7 Hz,1H), 2.26-2.17 (m, 2H), 2.01 (d, J=6.5 Hz, 4H), 1.89-1.80 (m, 6H), 1.65(d, J=5.7 Hz, 2H), 1.43 (s, 3H), 1.35 (s, 3H).

Example 174[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]azetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using azetidine hydrochloride and hunig's base to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₅H₄₁ClN₃O₇S[M−H]⁺: m/z=682.24/684.24; Found: 682.7/684.7. ¹H NMR (600 MHz, CDCl₃) δ7.69 (d, J=8.5 Hz, 1H), 7.41 (d, J=28.7 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H),7.07 (d, J=1.6 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.02 (s, 1H), 5.69(dd, J=15.6, 5.6 Hz, 1H), 5.34 (d, J=2.9 Hz, 1H), 5.16 (s, 1H), 4.02(ddd, J=21.9, 18.8, 7.6 Hz, 6H), 3.82 (s, 1H), 3.68 (d, J=14.5 Hz, 1H),3.49 (s, 1H), 3.39-2.96 (m, 2H), 2.81-2.72 (m, 2H), 2.63 (d, J=10.3 Hz,1H), 2.34 (qd, J=9.5, 3.2 Hz, 1H), 2.26-2.18 (m, 2H), 2.03-1.96 (m, 4H),1.91 (dd, J=8.8, 4.0 Hz, 2H), 1.82-1.74 (m, 3H), 1.38 (s, 3H), 1.25 (s,3H).

Example 175[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-methylpiperazine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (2R)-2-methylpiperazine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₇H₄₈ClN₄O₇S[M+H]⁺: m/z=727.29/729.28; Found: 727.5/729.5. ¹H NMR (600 MHz, CDCl₃) δ9.65 (s, 1H), 7.63 (dd, J=34.1, 7.2 Hz, 1H), 7.41 (d, J=25.4 Hz, 1H),7.19-7.04 (m, 2H), 6.93 (d, J=35.6 Hz, 2H), 5.85 (dd, J=202.2, 33.8 Hz,1H), 5.48-5.05 (m, 1H), 4.31-3.64 (m, 7H), 3.61-3.41 (m, 1H), 3.31 (d,J=14.6 Hz, 1H), 3.19-2.98 (m, 2H), 2.76 (ddd, J=22.2, 17.3, 4.6 Hz, 5H),2.34 (d, J=7.6 Hz, 2H), 2.27-2.18 (m, 1H), 2.03-1.88 (m, 4H), 1.84-1.70(m, 4H), 1.63 (d, J=9.9 Hz, 2H), 1.38 (s, 3H), 1.26 (d, J=8.7 Hz, 3H),1.10 (s, 3H).

Example 176[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3S)-3-methylpiperazine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (2S)-2-methylpiperazine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₇H₄₈ClN₄O₇S[M+H]⁺: m/z=727.29/729.28; Found: 727.5/729.5. ¹H NMR (500 MHz, CDCl₃) δ7.67 (d, J=8.5 Hz, 1H), 7.48 (d, J=7.1 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H),7.09 (dd, J=6.9, 2.2 Hz, 1H), 6.97 (d, J=8.1 Hz, 2H), 5.71 (s, 2H), 5.35(dd, J=5.7, 3.9 Hz, 2H), 4.13 (t, J=11.9 Hz, 2H), 4.03 (dd, J=22.2, 8.6Hz, 2H), 3.83-3.64 (m, 2H), 3.44 (d, J=14.9 Hz, 1H), 3.35 (d, J=14.6 Hz,1H), 3.26-3.12 (m, 1H), 3.00 (d, J=15.0 Hz, 1H), 2.82-2.72 (m, 4H), 2.54(s, 1H), 2.38 (s, 1H), 2.26-2.15 (m, 1H), 1.97 (dd, J=42.5, 8.6 Hz, 4H),1.86-1.74 (m, 4H), 1.63 (dd, J=19.1, 9.7 Hz, 2H), 1.48 (t, J=12.2 Hz,1H), 1.42 (s, 3H), 1.35 (s, 3H), 1.07 (s, 3H).

Example 177[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-(2-pyridyl)piperazine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 1-(2-pyridyl)piperazine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₄₁H₄₉ClN₅₀₇S[M+H]⁺: m/z=790.3/792.3; Found: 790.3/792.3. ¹H NMR (600 MHz, CDCl₃) δ9.13 (s, 1H), 8.28 (d, J=4.8 Hz, 1H), 7.82-7.73 (m, 1H), 7.67 (d, J=8.5Hz, 1H), 7.49 (dd, J=8.3, 2.2 Hz, 1H), 7.18 (dd, J=8.5, 2.2 Hz, 1H),7.09 (d, J=2.2 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H),6.90-6.77 (m, 2H), 6.01-5.67 (m, 2H), 5.56-5.21 (m, 2H), 4.29-4.02 (m,3H), 3.83-3.70 (m, 6H), 3.51-3.31 (m, 2H), 3.21 (dd, J=15.1, 9.7 Hz,1H), 2.84-2.73 (m, 4H), 2.48-2.31 (m, 1H), 2.28-2.19 (m, 1H), 2.10-1.91(m, 4H), 1.83 (ddd, J=25.5, 18.9, 9.2 Hz, 3H), 1.72-1.59 (m, 2H), 1.44(s, 3H), 1.36 (s, 3H).

Example 178[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15λ{circumflexover ( )}6-thia-1,14-diazatetracyclo[14.7.2.0{circumflex over( )}3,6.0{circumflex over( )}19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[2-(3-pyridyl)ethyl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 3-(2-aminoethyl)pyridine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₉H₄₆ClN₄O₇S[M+H]⁺: m/z=749.28/751.28; Found: 749.5/751.4. ¹H NMR (500 MHz, DMSO-d₆)δ 8.58 (s, 2H), 7.96 (d, J=7.4 Hz, 1H), 7.62 (dd, J=22.2, 7.3 Hz, 2H),7.33-7.23 (m, 2H), 7.19 (d, J=1.9 Hz, 1H), 7.12 (t, J=5.6 Hz, 1H),7.06-6.96 (m, 2H), 6.92 (s, 1H), 5.81-5.26 (m, 2H), 5.01 (d, J=91.1 Hz,1H), 4.11 (dd, J=43.7, 12.2 Hz, 3H), 3.90 (dd, J=14.3, 5.9 Hz, 2H),2.95-2.60 (m, 6H), 2.17-1.45 (m, 10H), 1.40 (s, 3H), 1.24 (s, 6H).

Example 179[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-(2,2-difluoroethyl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 2,2-difluoroethanamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₄H₄₁ClF₂N₃O₇S[M+H]⁺: m/z=708.23/710.23; Found: 708.4/710.3. ¹H NMR (500 MHz, DMSO-d₆)δ 11.66 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H),7.35-7.13 (m, 4H), 7.05 (t, J=19.8 Hz, 2H), 6.51 (s, 1H), 6.27-5.57 (m,2H), 5.33 (t, J=4.7 Hz, 1H), 5.04 (s, 1H), 4.33-3.72 (m, 3H), 2.85-2.64(m, 3H), 2.15-1.44 (m, 10H), 1.39 (s, 2H), 1.24 (s, 8H).

Example 180[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-(2-morpholinoethyl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 4-(2-aminoethyl)morpholine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₈H₅₀ClN₄O₈S[M+H]⁺: m/z=757.31/759.30; Found: 757.5/759.2.

Example 181[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-isopropylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using isopropylamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₅H₄₅ClN₃O₇S[M+H]⁺: m/z=686.26/688.26; Found: 686.8/688.8. ¹H NMR (600 MHz, CDCl₃) δ8.97 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.1 Hz, 1H), 7.17(dd, J=8.5, 2.2 Hz, 1H), 7.08 (d, J=1.7 Hz, 2H), 6.99 (d, J=8.3 Hz, 1H),5.82-5.60 (m, 2H), 5.15 (s, 1H), 4.64 (d, J=7.0 Hz, 1H), 4.13 (dd,J=26.0, 12.2 Hz, 3H), 3.80 (s, 3H), 3.52-3.07 (m, 3H), 2.86-2.63 (m,3H), 2.35 (d, J=40.1 Hz, 1H), 2.07-1.71 (m, 7H), 1.64 (d, J=10.1 Hz,1H), 1.42 (s, 3H), 1.37 (s, 3H), 1.17 (d, J=6.3 Hz, 6H).

Example 182[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-isobutylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using isobutylamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₆H₄₇ClN₃O₇S[M+H]⁺: m/z=700.27/702.27; Found: 700.8/702.6. ¹H NMR (600 MHz, CDCl₃) δ9.00 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.1 Hz, 1H), 7.17(dd, J=8.5, 2.2 Hz, 1H), 7.07 (dd, J=10.3, 1.9 Hz, 2H), 6.99 (d, J=8.3Hz, 1H), 5.88-5.57 (m, 2H), 5.20 (s, 1H), 4.91 (t, J=5.6 Hz, 1H),4.27-4.04 (m, 3H), 3.85-3.64 (m, 2H), 3.52-3.28 (m, 2H), 3.23-3.12 (m,1H), 3.01 (dd, J=13.5, 6.9 Hz, 2H), 2.77 (dd, J=10.5, 5.2 Hz, 3H), 2.37(dd, J=8.7, 3.9 Hz, 1H), 2.08-1.70 (m, 7H), 1.62 (d, J=9.6 Hz, 2H), 1.42(s, 3H), 1.37 (s, 3H), 0.92 (d, J=6.7 Hz, 6H).

Example 183[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-(cyclopropylmethyl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using cyclopropylmethylamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₆H₄₅ClN₃O₇S[M+H]⁺: m/z=698.27/700.27; Found: 698.3/700.1.

Example 184[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-cyclobutylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using cyclobutylamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₆H₄₅ClN₃O₇S[M+H]⁺: m/z=698.27/700.27; Found: 698.4/700.3. ¹H NMR (600 MHz, CDCl₃) δ9.00 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.1 Hz, 1H), 7.17(dd, J=8.5, 2.2 Hz, 1H), 7.07 (dd, J=10.3, 1.9 Hz, 2H), 6.99 (d, J=8.3Hz, 1H), 5.88-5.57 (m, 2H), 5.20 (s, 1H), 4.91 (t, J=5.6 Hz, 1H),4.27-4.04 (m, 3H), 3.85-3.64 (m, 2H), 3.52-3.28 (m, 2H), 3.23-3.12 (m,1H), 3.01 (dd, J=13.5, 6.9 Hz, 2H), 2.77 (dd, J=10.5, 5.2 Hz, 3H), 2.37(dd, J=8.7, 3.9 Hz, 1H), 2.08-1.70 (m, 7H), 1.62 (d, J=9.6 Hz, 2H), 1.42(s, 3H), 1.37 (s, 3H), 0.92 (d, J=6.7 Hz, 6H).

Example 185[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-tetrahydropyran-4-ylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 4-aminotetrahydropyran to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₇H₄₇ClN₃O₈S[M+H]⁺: m/z=728.28/730.28; Found: 728.3/730.0. ¹H NMR (600 MHz, DMSO-d₆)δ 11.66 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.40-6.73 (m, 7H), 6.53 (s,1H), 5.51 (dd, J=178.9, 11.3 Hz, 2H), 5.02 (s, 1H), 4.28-3.72 (m, 6H),3.55 (s, 1H), 2.73 (dd, J=24.8, 16.6 Hz, 3H), 2.12-1.49 (m, 12H),1.43-1.09 (m, 11H).

Example 186[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-isopropylpiperazine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 1-isopropylpiperazine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₉H₅₂ClN₄O₇S[M+H]⁺: m/z=755.32/757.31; Found: 755.5/757.4. ¹H NMR (600 MHz, CDCl₃) δ12.87 (s, 1H), 9.15 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.47 (d, J=7.6 Hz,1H), 7.18 (dd, J=8.5, 2.0 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.00 (d,J=8.3 Hz, 1H), 6.86 (s, 1H), 5.90 (t, J=20.4 Hz, 2H), 5.43-5.18 (m, 1H),4.47-4.01 (m, 5H), 3.89-3.28 (m, 9H), 3.25-2.59 (m, 6H), 2.29 (dt,J=15.3, 8.3 Hz, 2H), 2.17-1.91 (m, 4H), 1.89-1.80 (m, 4H), 1.35 (s,10H).

Example 187[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-(oxetan-3-yl)piperazine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using 1-(oxetan-3-yl)piperazine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₉H₅₀ClN₄O₈S[M+H]⁺: m/z=769.30/71.29; Found: 769.7/771.6. ¹H NMR (600 MHz, CDCl₃) δ9.13 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.52-7.40 (m, 1H), 7.18 (dd,J=8.5, 2.2 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.88(d, J=2.0 Hz, 1H), 6.01-5.74 (m, 2H), 5.54-5.25 (m, 4H), 4.77 (ddd,J=42.9, 9.0, 4.2 Hz, 3H), 4.31-4.07 (m, 4H), 3.93 (dd, J=33.3, 27.0 Hz,3H), 3.82-3.29 (m, 7H), 3.19 (dd, J=15.2, 10.0 Hz, 1H), 3.03-2.57 (m,7H), 2.44-2.18 (m, 5H), 1.45 (s, 6H).

Example 188[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-cyclopropylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using cyclopropylamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₅H₄₃ClN₃O₇S[M+H]⁺: m/z=684.24/686.24; Found: 684.4/686.1. ¹H NMR (300 MHz, CDCl₃) δ9.04 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.49 (dd, J=8.3, 2.1 Hz, 1H), 7.17(dd, J=8.5, 2.3 Hz, 1H), 7.11-6.89 (m, 3H), 5.67 (dd, J=16.0, 3.5 Hz,2H), 5.10 (d, J=55.9 Hz, 1H), 4.32-3.97 (m, 3H), 3.90-3.01 (m, 6H),2.93-2.16 (m, 5H), 2.08-1.72 (m, 7H), 1.64 (s, 1H), 1.43 (s, 3H), 1.36(s, 3H), 0.72 (dd, J=6.7, 5.0 Hz, 2H), 0.54 (s, 2H).

Example 189[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-methylpiperazine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using methylpiperazine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₇H₄₈ClN₄O₇S[M+H]⁺: m/z=727.30/729.29; Found: 727.6/729.2. ¹H NMR (499 MHz, CDCl₃) δ7.67 (d, J=8.5 Hz, 1H), 7.54-7.41 (m, 1H), 7.17 (dd, J=8.5, 2.3 Hz, 1H),7.13-7.04 (m, 1H), 6.98 (t, J=6.1 Hz, 2H), 6.17-5.55 (m, 2H), 5.32 (s,2H), 4.12 (dd, J=25.4, 12.1 Hz, 3H), 3.85-3.08 (m, 9H), 2.93-2.64 (m,3H), 2.60-2.14 (m, 9H), 2.09-1.92 (m, 5H), 1.82 (s, 2H), 1.43 (s, 3H),1.36 (s, 3H).

Example 190[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-hydroxypiperidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using piperidin-4-ol to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₇H₄₇ClN₃O₈S[M+H]⁺: m/z=728.28/730.28; Found: 728.4/729.9. ¹H NMR (500 MHz, DMSO-d₆)δ 11.69 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.20 (ddd, J=109.1, 20.0, 12.8Hz, 6H), 6.57 (s, 1H), 5.74 (s, 2H), 5.20 (s, 1H), 4.77 (d, J=3.5 Hz,1H), 3.92 (ddd, J=188.7, 35.2, 15.1 Hz, 8H), 2.96-2.68 (m, 4H), 1.84(dd, J=111.2, 52.7 Hz, 11H), 1.31 (t, J=57.5 Hz, 10H).

Example 191[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-(2-methoxyethyl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 2-methoxyethylamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₅H₄₅ClN₃O₈S[M+H]⁺: m/z=702.26/704.26; Found: 702.4/704.3. ¹H NMR (500 MHz, DMSO-d₆)δ 11.72 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.40-7.19 (m, 3H), 7.05 (d,J=48.1 Hz, 3H), 6.57 (s, 1H), 5.95-5.33 (m, 2H), 5.07 (s, 1H), 4.39-3.76(m, 4H), 3.59 (d, J=14.9 Hz, 2H), 3.28 (s, 3H), 3.16 (s, 2H), 2.96-2.64(m, 3H), 2.16-1.50 (m, 9H), 1.44 (s, 2H), 1.25 (d, J=43.6 Hz, 7H).

Example 192[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-(oxetan-3-yl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using oxetan-3-amine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₅H₄₃ClN₃O₈S[M+H]⁺: m/z=700.24/702.24; Found: 700.3/702.3. ¹H NMR (600 MHz, CDCl₃) δ8.97 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.49 (dd, J=26.7, 25.2 Hz, 1H),7.18 (dd, J=8.5, 2.2 Hz, 1H), 7.07 (d, J=13.5 Hz, 2H), 7.01 (d, J=8.3Hz, 1H), 5.94-5.64 (m, 2H), 5.56-5.12 (m, 4H), 4.98-4.79 (m, 3H), 4.56(d, J=6.0 Hz, 2H), 4.13 (dd, J=27.7, 12.2 Hz, 3H), 3.75 (dd, J=53.1,12.3 Hz, 2H), 3.53-3.10 (m, 2H), 2.90-2.65 (m, 3H), 2.49-2.28 (m, 1H),2.29-2.14 (m, 2H), 2.01 (d, J=5.4 Hz, 4H), 1.86 (d, J=10.0 Hz, 1H), 1.43(s, 3H), 1.37 (s, 3H).

Example 193[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[2-(1-piperidyl)ethyl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using 1-(2-aminoethyl)-piperidine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₉H₅₂ClN₄O₇S[M+H]⁺: m/z=755.33/757.32; Found: 755.5/757.4. ¹H NMR (600 MHz, CDCl₃) δ12.22 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.17 (dd,J=8.5, 2.2 Hz, 1H), 7.08 (s, 1H), 7.03-6.86 (m, 2H), 5.81 (s, 1H), 5.63(dd, J=15.4, 4.6 Hz, 1H), 5.42-5.24 (m, 2H), 5.18 (s, 1H), 4.12 (dd,J=24.6, 12.2 Hz, 3H), 4.04-3.79 (m, 2H), 3.78-3.55 (m, 5H), 3.50-2.98(m, 5H), 2.93-2.53 (m, 6H), 2.49-2.28 (m, 1H), 2.28-2.12 (m, 2H),2.08-1.96 (m, 6H), 1.40 (s, 4H), 1.36 (s, 5H).

Example 194[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-[2-(methylamino)ethyl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using N¹,N²-dimethylethane-1,2-diamine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₆H₄₈ClN₄O₇S[M+H]⁺: m/z=715.30/717.29; Found: 715.5/717.5. ¹H NMR (500 MHz, DMSO-d₆)δ 11.61 (s, 1H), 8.42 (s, 2H), 7.65 (d, J=8.3 Hz, 1H), 7.26 (dd, J=8.4,2.3 Hz, 2H), 7.19 (d, J=2.0 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.95 (s,1H), 5.69 (s, 2H), 5.29 (dd, J=49.6, 44.7 Hz, 1H), 4.32-3.87 (m, 3H),3.56 (d, J=14.5 Hz, 2H), 2.82 (ddd, J=56.1, 35.7, 24.1 Hz, 9H), 2.59 (s,3H), 2.16-1.57 (m, 8H), 1.39 (s, 4H), 1.23 (d, J=10.5 Hz, 6H).

Example 195[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3S)-3-methoxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 using (3S)-3-methoxypyrrolidine to replace1-(2-methoxyethyl)piperazine in Step 2. LCMS calc. for C₃₇H₄₇ClN₃O₈S[M+H]⁺: m/z=728.27/730.27; Found: 728.5/730.5. ¹H NMR (300 MHz, CDCl₃) δ7.68 (d, J=8.5 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.13 (dd, J=8.4, 2.4 Hz,1H), 7.06 (d, J=2.2 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.85 (d, J=8.2 Hz,1H), 6.10 (br, 1H), 5.70 (ddd, J=15.8, 10.4, 5.4 Hz, 1H), 5.22-5.14 (m,1H), 4.12-3.92 (m, 4H), 3.86 (d, J=16.1 Hz, 2H), 3.66 (t, J=13.7 Hz,2H), 3.52-3.40 (m, 4H), 3.34 (s, 3H), 3.28 (s, 2H), 3.09 (q, J=12.3 Hz,2H), 2.78-2.70 (m, 4H), 2.31 (d, J=8.0 Hz, 1H), 2.01-1.92 (m, 4H),1.80-1.72 (m, 3H), 1.36 (s, 3H), 1.31 (s, 3H).

Example 196(3R,6R,12S,22S)-6′-Chloro-11,12-dimethyl-15,15-dioxo-spiro[8,20-dioxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-16,18,24-triene-22,1′-tetralin]-10,13-dione

Step 1: tert-butyl2-[[(R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]acetate

To a solution of(3S)-6′-chloro-5-[[(1R,2R)-2-(hydroxymethyl)cyclobutyl]methyl]-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(300.0 mg, 0.42 mmol, Intermediate 3 Step 2) in THF (15 mL) was addedpotassium tert-butoxide (93.86 mg, 0.84 mmol) at 20° C. The mixture wasstirred at r.t. for 30 min., and t-butyl bromoacetate (163.15 mg, 0.84mmol) was then added. The resulting mixture was stirred at r.t.overnight. LCMS showed full conversion of starting material. Thereaction was quenched by water (5 mL), and extracted with EtOAc (20mL×3). The combined organic layers were dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column (12 g) withEtOAc/Heptanes (3% to 40%) to afford tert-butyl2-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]acetate(280 mg, 80.5% yield) as a white solid. LCMS calc. for C₄₆H₅₆ClN₂O₈S[M+H]⁺: m/z=831.34/833.34; Found: 831.06/832.45.

Step 2:2-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]aceticacid

To a solution of tert-butyl2-[[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]acetate(280.0 mg, 0.34 mmol) in DCM (3 mL) was added TFA (3.0 mL, 39.2 mmol) at40° C. The reaction mixture was stirred for 4 h. LCMS analysis indicatedthe completion of reaction. The reaction was diluted with EtOAc (10 mL),and adjusted to 7-8 pH with saturated aqueous Na₂CO₃ solution. Thelayers were separated, and the aqueous layer was extracted with EtOAc(10 mL×3). The combined organic layers were dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting solutionwas concentrated under reduced pressure and the residue was purified byflash chromatography system on a silica gel column (12 g) withEtOAc/Heptanes (3% to 60%) to afford2-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]aceticacid (152 mg, 84.4% yield) as a white solid. LCMS calc. forC₂₆H₃₂ClN₂O₆S [M+H]⁺: m/z=535.16/537.16; Found: 534.8/536.6.

Step 3: methyl2-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]acetate

To a stirred solution of2-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]aceticacid (195.0 mg, 0.36 mmol) in DMF (5 mL) was added K₂CO₃ (100.59 mg,0.73 mmol) and iodomethane (103.46 mg, 0.73 mmol). The resulting mixturewas stirred at r.t. for 4 h. LCMS showed full conversion of startingmaterial. EtOAc (10 mL) was added and the layers were separated, thenthe aqueous layer was adjusted pH to 1-2 with aq. HCl (1 N), andextracted with EtOAc (20 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column (12g) with EtOAc/Heptanes (2% to 50%) to afford methyl2-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]acetate(159 mg, 79.5% yield) as a white solid. LCMS calc. for C₂₇H₃₄ClN₂O₆S[M+H]⁺: m/z=549.17/551.17; Found: 548.9/550.6.

Step 4: methyl2-[[(1R,2R)-2-[[(3S)-7-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]acetate

A mixture of (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid(77.73 mg, 0.38 mmol), methyl2-[[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]acetate(70.0 mg, 0.13 mmol), EDCI (73.32 mg, 0.38 mmol) and DMAP (77.4 mg, 0.76mmol) in DCM (3 mL) was stirred at r.t. overnight. LCMS analysisindicated the completion of reaction. The reaction was diluted with DCM(10 mL), washed with 1 N HCl (2 mL) and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure The residue waspurified by flash chromatography on a silica gel column (12 g) withEtOAc/Heptanes (3% to 60%) to afford methyl2-[[(1R,2R)-2-[[(3S)-7-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]acetate(75 mg, 80.1% yield) as a white solid. LCMS calc. for C₃₆H₄₉ClN₃O₉S[M+H]⁺: m/z=734.28/736.28; Found: 733.9/736.3.

Step 5:2-[[(1R,2R)-2-[[(3S)-7-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]aceticacid

To a stirred solution of methyl2-[[(1R,2R)-2-[[(3S)-7-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]acetate(75.0 mg, 0.10 mmol) in THF (0.50 mL) and methanol (0.50 mL) was addedlithium hydroxide monohydrate (12.87 mg, 0.31 mmol) in water (0.50 mL).The resulting mixture was stirred at r.t. for 4 h. LCMS showed fullconversion of starting material. THF and MeOH were partially removed ona rotary evaporator, and the aqueous layer was adjusted pH to 1-2 withaq. HCl (1 N) and extracted with EtOAc (10 mL×3). The combined organiclayers were dried over sodium sulfate, filtered and concentrated underreduced pressure to afford2-[[(1R,2R)-2-[[(3S)-7-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]aceticacid (64 mg, 87% yield) as a white solid. LCMS calc. for C₃₅H₄₇ClN₃O₉S[M+H]⁺: m/z=720.26/722.26; Found: 720.0/721.6.

Step 6:2-[[(1R,2R)-2-[[(3S)-6′-chloro-7-[[(2S)-2-(methylamino)propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]aceticacid

2-[[(1R,2R)-2-[[(3S)-7-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]-sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]-cyclobutyl]methoxy]aceticacid (64.0 mg, 0.09 mmol) was dissolved in 2N HCl in EtOAc solution (0.0mL, 0.09 mmol), and stirred at r.t. for 6 h. The reaction wasconcentrated under reduced pressure, and the residue was added lithiumhydroxide monohydrate (3.73 mg, 0.09 mmol) in THF (0.50 mL), water (0.50mL) and methanol (0.50 mL). After 2 h, LCMS analysis indicated thecompletion of reaction. The reaction mixture was concentrated underreduced pressure to afford2-[[(1R,2R)-2-[[(3S)-6′-chloro-7-[[(2S)-2-(methylamino)propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]methoxy]aceticacid (51 mg, 92.6% yield) as a white solid. LCMS calc. for C₃₀H₃₉ClN₃O₇S[M+H]⁺: m/z=620.22/622.22; Found: 619.9/622.1.

Step 7:(3R,6R,12S,22S)-6′-chloro-11,12-dimethyl-15,15-dioxo-spiro[8,20-dioxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-16,18,24-triene-22,1′-tetralin]-10,13-dione

To a stirred solution of2-[[(1R,2R)-2-[[(3S)-6′-chloro-7-[[(2S)-2-(methylamino)-propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]-cyclobutyl]methoxy]aceticacid (26.0 mg, 0.04 mmol) in DMF (2 mL) was added HATU (31.88 mg, 0.08mmol) and DIPEA (0.01 mL, 0.08 mmol) at 20° C. After 1 h, LCMS analysisindicated the full conversion of starting material to the desiredproduct. The reaction was quenched by water (5 mL), and extracted withEtOAc (10 mL×3). The combined organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column (12 g) withEtOAc/Heptanes (2% to 60%). The desired fractions were collected, andfurther purified by prep-HPLC on a C18 column (30×250 mm, 10 μm) withMeCN/H₂O (20 to 100%) to afford(3R,6R,12S,22S)-6′-chloro-11,12-dimethyl-15,15-dioxo-spiro[8,20-dioxa-15-thia-1,11,14-triazatetracyclo-[14.7.2.03,6.019,24]pentacosa-16,18,24-triene-22,1′-tetralin]-10,13-dione(6.2 mg, 0.0103 mmol, 24.56% yield) as a white solid. LCMS calc602.20/604.20; Found 602.28/604.25.

Example 197(3R,6R,12S,22S)-6′-Chloro-12-methyl-15,15-dioxo-spiro[8,20-dioxa-15-thia-1,11,14-triazatetracyclo[14.7.2.0-3,6.0-19,24]pentacosa-16,18,24-triene-22,1′-tetralin]-10,13-dione

This compound was prepared using procedures analogous to those describedfor Example 196 Step 4-7 using(2S)-2-(tert-butoxycarbonylamino)propanoic acid to replace(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid in Step 4. LCMScalc. for C₂₉H₃₅ClN₃O₆S [M+H]⁺: m/z=588.19/590.19; Found 588.6/590.6. ¹HNMR (400 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H),7.22 (s, 1H), 7.13 (dd, J=8.2, 2.2 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 6.80(d, J=8.1 Hz, 1H), 5.48-5.23 (m, 1H), 4.39 (d, J=8.6 Hz, 1H), 4.06-3.82(m, 4H), 3.75 (d, J=14.2 Hz, 2H), 3.46 (s, 2H), 3.34 (d, J=14.4 Hz, 1H),3.09 (d, J=13.5 Hz, 1H), 2.81 (d, J=25.2 Hz, 2H), 1.97 (s, 3H), 1.72(ddd, J=42.0, 16.7, 8.4 Hz, 5H), 1.37 (d, J=7.2 Hz, 5H).

Example 198[(3R,6R,7R,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.0-3,6.0-19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

Step 1:[(1R)-1-[(1R,2R)-2-[[(3S)-7-[[2-(allylamino)-2-methyl-propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 42 Step 2 using[(1R)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate (Intermediate 10) and3-allyl-4,4-dimethyl-oxazolidine-2,5-dione (Example 42 Step 1). LC-MS:calc. for C₃₆H₄₈ClN₄O₆S [M+H]⁺: m/z=699.3/701.3; Found: 699.5/701.5.

Step 2:[(3R,6R,7R,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.0˜3,6.0˜19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 26 Step 4 using[(1R)-1-[(1R,2R)-2-[[(3S)-7-[[2-(allylamino)-2-methyl-propanoyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate. LCMS calc. for C₃₄H₄₄ClN₄O₆S [M+H]⁺:m/z=671.3/673.3; Found: 671.9/673.8.

Example 199[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]morpholine-4-carboxylate

Step 1.[(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]phenyl carbonate

To a solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(680.0 mg, 1.11 mmol, Example 43) in pyridine (0.89 mL, 11.07 mmol) wasadded phenyl chloroformate (0.69 mL, 5.54 mmol). The mixture was stirredat r.t. for 1 h. LCMS showed the full conversion of the startingmaterial into the desired product. The mixture was concentrated underreduced pressure and the residue was purified by flash chromatography ona silica gel column with EA:Hep (50% to 100%) to afford[(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]phenyl carbonate (810 mg, 99.6% yield).

Step 2:[(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]morpholine-4-carboxylate

To a solution of[(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]phenyl carbonate (40.0 mg, 0.05 mmol) in MeCN (1 mL) was addedmorpholine (47.46 mg, 0.54 mmol). Reaction was stirred for 14 h at 75°C. LCMS showed the conversion of the starting material into the desiredproduct. The mixture was concentrated and purified by prep-HPLC on a C18column (15% to 100% MeCN/H₂O) to afford[(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]morpholine-4-carboxylate (15 mg, 37.9% yield). LCMS calcd. forC₃₇H₄₈ClN₄O₇S [M+H]⁺: m/z=727.29/729.29; Found 727.4/729.4. ¹H NMR (300MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.53-7.43 (m, 1H), 7.19 (dd,J=8.5, 2.4 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.83(s, 1H), 5.86 (s, 1H), 5.70 (d, J=15.7 Hz, 1H), 5.39 (s, 1H), 4.17 (d,J=12.2 Hz, 1H), 4.06 (d, J=12.1 Hz, 1H), 3.72 (d, J=5.6 Hz, 6H), 3.50 (m6H), 3.35 (d, J=14.8 Hz, 1H), 3.09 (dd, J=15.0, 10.9 Hz, 1H), 2.87-2.73(m, 3H), 2.29 (s, 3H), 1.99 (d, J=12.4 Hz, 2H), 1.83 (q, J=10.1, 9.5 Hz,2H), 1.68 (dt, J=18.6, 9.5 Hz, 1H), 1.45 (d, J=12.8 Hz, 1H), 1.31 (d,J=24.9 Hz, 6H), 1.12 (s, 3H).

Example 200[(3R,6R,7R,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

To a solution of[(3R,6R,7R,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.0˜3,6.0˜19,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate (10.0 mg, 0.01 mmol, Example 197) in DCE (0.50 mL)was added 37% formaldehyde aqueous solution (0.01 mL, 0.30 mmol). Themixture was stirred at r.t. for 2 h., then NaBH₃CN (11.27 mg, 0.30 mmol)in methanol (0.10 mL) was added. The reaction mixture was stirred atr.t. for 6 h. The reaction was quenched by sat. NH₄Cl aqueous solution(5 mL), and extracted with EtOAc (10 mL×3). The combined organic layerswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC on a C18 column withMeCN/H₂O (20% to 100%) to afford[(3R,6R,7R,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate (6.3 mg, 61.7% yield) as a white solid. LCMS calc.for C₃₅H₄₆ClN₄O₆S [M+H]⁺: m/z=685.3/687.3; Found 685.8/687.3. ¹H NMR(600 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H), 7.52 (d, J=15.5 Hz, 1H), 7.18(dd, J=8.6, 2.3 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H),6.83 (s, 1H), 5.92 (dt, J=12.7, 6.0 Hz, 1H), 5.41-5.25 (m, 1H), 5.07 (s,1H), 4.08 (t, J=16.8 Hz, 2H), 3.73 (d, J=14.7 Hz, 1H), 3.36 (s, 1H),3.06 (dd, J=15.2, 10.7 Hz, 1H), 2.92 (s, 4H), 2.84-2.72 (m, 3H), 2.52(s, 1H), 2.28 (s, 2H), 2.22 (t, J=7.7 Hz, 1H), 2.08-1.90 (m, 5H), 1.83(s, 3H), 1.72-1.61 (m, 3H), 1.43 (t, J=13.1 Hz, 2H), 1.32 (d, J=12.4 Hz,3H), 1.26 (d, J=8.6 Hz, 3H).

Example 201[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-cyclobutylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using cyclobutylamine to replace morpholine. LCMScalc. for C₃₇H₄₈ClN₄O₆S [M+H]⁺: m/z=711.30/713.30; Found: 711.7/713.8.¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.3, 2.0Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.09 (d, J=2.1 Hz, 1H), 6.98 (d,J=8.4 Hz, 1H), 6.89 (s, 1H), 5.89 (d, J=15.5 Hz, 1H), 5.67 (d, J=14.4Hz, 1H), 5.44 (s, 1H), 5.28 (d, J=17.7 Hz, 1H), 4.14 (dt, J=35.4, 10.4Hz, 3H), 3.70 (d, J=14.7 Hz, 1H), 3.39 (dd, J=28.7, 14.8 Hz, 2H),3.14-2.97 (m, 1H), 2.81 (dd, J=15.8, 8.0 Hz, 5H), 2.46-2.13 (m, 5H),2.09-1.89 (m, 5H), 1.89-1.77 (m, 4H), 1.77-1.52 (m, 4H), 1.45 (d, J=12.6Hz, 1H), 1.35 (s, 3H), 1.11 (s, 3H).

Example 202[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-[(3S)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 32) in Step 2 and (3S)—N-methyltetrahydrofuran-3-aminehydrochloride in Step 1. LCMS calc. for C₃₇H₄₇ClN₃O₈S [M+H]⁺:m/z=728.27/730.27; Found: 728.4/730.1. ¹H NMR (300 MHz, CDCl₃) δ 9.12(s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.1 Hz, 1H), 7.19 (dd,J=8.6, 2.2 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.01 (s, 1H), 6.99-6.95 (m,1H), 5.83 (dd, J=5.9, 3.4 Hz, 1H), 5.73 (dd, J=15.7, 5.2 Hz, 1H), 5.33(q, J=4.3, 3.9 Hz, 1H), 4.91 (s, 1H), 4.12 (t, J=6.3 Hz, 2H), 4.09-4.04(m, 1H), 3.78 (s, 2H), 3.69 (d, J=8.3 Hz, 1H), 3.50-3.32 (m, 2H), 3.23(dd, J=15.1, 9.3 Hz, 1H), 2.90 (s, 3H), 2.81-2.76 (m, 3H), 2.40 (dd,J=8.9, 3.5 Hz, 1H), 2.24 (dd, J=9.5, 5.5 Hz, 1H), 2.04 (d, J=8.6 Hz,1H), 1.95 (d, J=10.1 Hz, 2H), 1.87-1.74 (m, 5H), 1.71-1.62 (m, 3H), 1.51(d, J=12.6 Hz, 1H), 1.44 (s, 3H), 1.37 (s, 3H).

Example 203[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using methylamine (40% in water) to replacemorpholine. LCMS calc. for C₃₄H₄₄ClN₄O₆S [M+H]⁺: m/z=671.27/673.27;Found: 671.7/673.6. ¹H NMR (499 MHz, DMSO-d₆) δ 7.63 (dd, J=8.5, 2.5 Hz,1H), 7.25 (dd, J=8.5, 2.4 Hz, 1H), 7.19-7.07 (m, 2H), 6.88-6.84 (m, 2H),6.07 (br, 1H), 5.81-5.66 (m, 1H), 5.17-5.12 (m, 1H), 3.58-3.49 (m, 1H),3.31-3.25 (m, 6H), 3.19-3.06 (m, 1H), 2.86-2.64 (m, 4H), 2.60 (d, J=4.6Hz, 2H), 2.55 (s, 3H), 2.37 (dt, J=3.8, 2.0 Hz, 1H), 2.00 (dt, J=12.2,3.9 Hz, 1H), 1.85 (s, 3H), 1.77-1.61 (m, 3H), 1.48-1.44 (m, 1H), 1.35(s, 3H), 1.28-1.10 (m, 5H).

Example 204[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-ethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using ethylamine (66-72% in water) to replacemorpholine. LCMS calc. for C₃₅H₄₆ClN₄O₆S [M+H]⁺: m/z=685.28/687.28;Found: 685.7/687.7. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H),7.51 (dd, J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.09 (d,J=2.0 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.88 (s, 1H), 5.90 (d, J=15.4 Hz,1H), 5.68 (d, J=15.7 Hz, 1H), 5.28 (s, 1H), 5.21 (s, 1H), 4.12 (dd,J=36.0, 12.1 Hz, 2H), 3.70 (d, J=14.5 Hz, 1H), 3.50-3.35 (m, 2H), 3.27(dd, J=13.5, 7.0 Hz, 2H), 3.16-2.97 (m, 1H), 2.81 (dd, J=14.7, 8.2 Hz,4H), 2.28 (s, 4H), 2.06-1.92 (m, 4H), 1.85 (s, 4H), 1.63 (dd, J=18.6,9.6 Hz, 1H), 1.45 (d, J=12.8 Hz, 1H), 1.35 (s, 3H), 1.22 (dd, J=16.2,9.0 Hz, 3H), 1.11 (s, 3H).

Example 205[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-(cyclopropylmethyl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using cyclopropyl methylamine to replacemorpholine. LCMS calc. for C₃₇H₄₈ClN₄O₆S [M+H]⁺: m/z=711.30/713.30;Found: 711.8/713.8. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H),7.51 (dd, J=8.3, 2.0 Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.09 (d,J=2.0 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.89 (s, 1H), 5.93 (d, J=15.4 Hz,1H), 5.68 (d, J=15.4 Hz, 1H), 5.40 (s, 1H), 5.26 (s, 1H), 4.12 (dd,J=36.4, 12.1 Hz, 2H), 3.70 (d, J=14.8 Hz, 1H), 3.39 (dd, J=25.6, 14.9Hz, 3H), 3.17-2.98 (m, 3H), 2.92-2.68 (m, 4H), 2.29 (s, 4H), 1.99 (d,J=11.2 Hz, 4H), 1.87 (d, J=16.2 Hz, 4H), 1.63 (dd, J=18.8, 9.3 Hz, 1H),1.45 (d, J=12.4 Hz, 1H), 1.35 (s, 3H), 1.10 (d, J=10.9 Hz, 3H),0.57-0.47 (m, 2H), 0.27 (q, J=4.7 Hz, 2H).

Example 206[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-(cyclopropylmethyl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using cyclopropylamine to replace morpholine.LCMS calc. for C₃₆H₄₆ClN₄O₆S [M+H]⁺: m/z=697.28/699.28; Found:697.7/699.8. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.50 (dd,J=8.3, 2.0 Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.09 (d, J=2.0 Hz,1H), 6.97 (d, J=8.3 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 5.85 (s, 1H), 5.68(d, J=16.0 Hz, 1H), 5.43 (s, 1H), 5.29 (s, 1H), 4.11 (dd, J=35.5, 12.1Hz, 2H), 3.70 (d, J=14.2 Hz, 1H), 3.38 (dd, J=25.8, 14.4 Hz, 2H),3.15-2.99 (m, 2H), 2.96-2.73 (m, 4H), 2.67 (s, 1H), 2.29 (s, 4H),2.07-1.89 (m, 4H), 1.85 (d, J=8.6 Hz, 4H), 1.63 (d, J=8.2 Hz, 1H), 1.45(d, J=12.5 Hz, 1H), 1.36 (s, 3H), 1.11 (s, 3H), 0.77 (d, J=5.4 Hz, 2H),0.59 (d, J=4.8 Hz, 2H).

Example 207[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-isopropylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using propan-2-amine to replace morpholine. LCMScalc. for C₃₆H₄₈ClN₄O₆S [M+H]⁺: m/z=699.30/701.30; Found: 699.8/701.7.¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.51 (dd, J=8.3, 2.0Hz, 1H), 7.19 (dd, J=8.6, 2.1 Hz, 1H), 7.09 (d, J=1.9 Hz, 1H), 6.98 (d,J=8.4 Hz, 1H), 6.89 (s, 1H), 5.89 (d, J=15.6 Hz, 1H), 5.68 (d, J=14.9Hz, 1H), 5.24 (s, 1H), 5.12 (s, 1H), 4.12 (dd, J=35.8, 12.1 Hz, 2H),3.86 (dd, J=13.6, 6.5 Hz, 1H), 3.70 (d, J=14.6 Hz, 1H), 3.39 (dd,J=28.1, 14.5 Hz, 2H), 3.13-2.99 (m, 1H), 2.80 (t, J=10.4 Hz, 6H), 2.28(s, 3H), 2.08-1.91 (m, 3H), 1.84 (d, J=4.3 Hz, 3H), 1.63 (dd, J=18.9,9.6 Hz, 1H), 1.45 (d, J=13.0 Hz, 1H), 1.35 (s, 3H), 1.23 (dd, J=11.4,6.6 Hz, 7H), 1.11 (s, 3H).

Example 208[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 by replacement of morpholine with(9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine which wasprepared in THF solution as following: a solution of(9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazinedihydrochloride (500.0 mg, 2.32 mmol) in methanol (1 mL) was treatedNaOMe (105.9 mg, 1.96 mmol) for 30 min. at r.t., concentrated underreduced pressure, re-dissolved in THF (1 mL) and filtered. LCMS calc.for C₄₀H₅₃ClN₅O₇S [M+H]⁺: m/z=782.33/784.33; Found 782.5/784.4. ¹H NMR(300 MHz, CDCl₃) δ 7.69 (dd, J=7.8, 4.1 Hz, 1H), 7.50 (dd, J=8.3, 2.1Hz, 1H), 7.19 (dd, J=8.6, 2.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.97 (d,J=8.3 Hz, 1H), 6.81 (s, 1H), 5.91-5.62 (m, 2H), 5.40 (s, 1H), 4.22-4.00(m, 4H), 3.88-3.65 (m, 5H), 3.48-3.22 (m, 4H), 3.10 (q, J=13.6, 11.8 Hz,3H), 2.89-2.70 (m, 7H), 2.28 (d, J=9.6 Hz, 6H), 1.99 (d, J=12.2 Hz, 4H),1.91-1.75 (m, 4H), 1.35 (s, 3H), 1.10 (s, 3H).

Example 209[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

Step 1:[(1S)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 42 Step 2 using[(1S)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate (Intermediate 9) and3-allyl-4,4-dimethyl-oxazolidine-2,5-dione (Example 42 Step 1). LCMScalc. for C₃₆H₄₈ClN₄O₆S [M+H]⁺: m/z=699.3/701.3; Found: 699.9/701.8.

Step 2:[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 26 Step 4 using[(1S)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]N,N-dimethylcarbamate. LCMS calc. for C₃₄H₄₄ClN₄O₆S [M+H]⁺:m/z=671.3/673.3; Found: 671.8/673.2.

Example 210[(3R,6R,7S,8E,22S)-6′-Chloro-11-ethyl-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 27 using[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate (Example 204) and acetaldehyde. LCMS calc. forC₃₆H₄₈ClN₄O₆S [M+H]⁺: m/z=699.30/701.30; Found: 699.69/701.66. ¹H NMR(300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.1 Hz, 1H),7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.09 (d, J=2.1 Hz, 1H), 6.97 (d, J=8.3 Hz,1H), 6.84 (d, J=2.0 Hz, 1H), 5.90 (dd, J=15.5, 8.3 Hz, 1H), 5.67 (d,J=15.5 Hz, 1H), 5.28 (s, 1H), 4.12 (dd, J=37.4, 12.1 Hz, 2H), 3.73 (d,J=14.7 Hz, 1H), 3.41 (dd, J=20.8, 15.1 Hz, 2H), 3.12 (s, 3H), 3.00 (d,J=7.3 Hz, 3H), 2.93-2.74 (m, 4H), 2.73-2.58 (m, 1H), 2.29-2.14 (m, 2H),1.99 (d, J=10.6 Hz, 4H), 1.91-1.74 (m, 4H), 1.66 (dd, J=18.7, 9.3 Hz,2H), 1.41 (d, J=7.3 Hz, 5H), 1.18 (s, 3H), 1.06 (t, J=7.1 Hz, 3H).

Example 211[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-11-propyl-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 27 using[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate (Example 204) and propionaldehyde. LCMS calc. forC₃₆H₄₈ClN₄O₆S [M+H]⁺: m/z=699.30/701.30; Found: 699.7/701.7. ¹H NMR (300MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 1.9 Hz, 1H), 7.19(dd, J=8.5, 2.1 Hz, 1H), 7.09 (d, J=1.9 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H),6.84 (d, J=1.9 Hz, 1H), 5.93 (dd, J=15.4, 8.5 Hz, 1H), 5.65 (d, J=15.7Hz, 1H), 5.28 (s, 1H), 4.12 (dd, J=37.7, 12.1 Hz, 2H), 3.73 (d, J=14.7Hz, 1H), 3.41 (t, J=16.2 Hz, 3H), 3.08 (dd, J=20.9, 10.1 Hz, 4H),3.02-2.90 (m, 4H), 2.78 (dt, J=15.9, 14.5 Hz, 4H), 2.48-2.36 (m, 1H),2.22 (d, J=8.4 Hz, 1H), 1.99 (d, J=10.9 Hz, 3H), 1.83 (dd, J=8.8, 4.5Hz, 3H), 1.68-1.59 (m, 2H), 1.48 (dt, J=11.9, 6.1 Hz, 3H), 1.38 (s, 3H),1.16 (s, 3H), 0.90 (t, J=7.3 Hz, 3H).

Example 212[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[(3S)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using (3S)-tetrahydrofuran-3-amine to replacemorpholine. LCMS calc. for C₃₇H₄₈ClN₄O₇S [M+H]⁺: m/z=727.29/729.29;Found: 727.4/729.5. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H),7.51 (dd, J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.08 (d,J=2.3 Hz, 1H), 7.02-6.87 (m, 2H), 6.09 (t, J=11.5 Hz, 1H), 5.90 (s, 1H),5.66 (d, J=16.1 Hz, 1H), 5.19 (s, 1H), 4.40-4.13 (m, 4H), 4.04 (d,J=12.1 Hz, 1H), 3.95 (d, J=9.5 Hz, 1H), 3.85-3.60 (m, 3H), 3.42 (d,J=13.5 Hz, 1H), 3.31 (d, J=14.7 Hz, 1H), 3.10-2.67 (m, 6H), 2.43-2.13(m, 4H), 2.09-1.70 (m, 5H), 1.61 (q, J=9.0 Hz, 1H), 1.33 (d, J=38.8 Hz,5H), 1.12 (s, 3H).

Example 213[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[2-(dimethylamino)ethyl]-N-methyl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using N,N,N′-trimethylethylenediamine to replacemorpholine. LCMS calc. for C₃₈H₅₃ClN₅O₆S [M+H]⁺: m/z=742.33/744.33;Found: 742.8/744.8. ¹H NMR (300 MHz, CDCl₃) δ 7.70 (d, J=8.5 Hz, 1H),7.50 (dd, J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.09 (d,J=2.3 Hz, 1H), 6.96 (dd, J=8.3, 2.3 Hz, 1H), 6.84 (d, J=2.3 Hz, 1H),6.06-5.85 (m, 1H), 5.78-5.65 (m, 1H), 5.31 (d, J=16.4 Hz, 1H), 4.16 (d,J=12.2 Hz, 1H), 4.11-4.00 (m, 1H), 3.78-3.56 (m, 2H), 3.51-3.23 (m, 3H),3.15-2.86 (m, 10H), 2.88-2.73 (m, 6H), 2.64-2.38 (m, 1H), 2.35-2.17 (m,6H), 2.01 (dt, J=10.8, 5.6 Hz, 3H), 1.66 (q, J=8.9, 8.5 Hz, 1H),1.51-1.23 (m, 6H), 1.13 (d, J=3.5 Hz, 3H).

Example 214[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-(dimethylamino)azetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 using 3-dimethylamino azetidine 2HCl salt and Hunig'sbase to replace morpholine. LCMS calc. for C₃₈H₅₁ClN₅O₆S [M+H]⁺:m/z=740.32/742.31; Found: 740.6/742.6. ¹H NMR (300 MHz, CDCl₃) δ 7.69(d, J=8.5 Hz, 1H), 7.51 (dd, J=8.3, 2.0 Hz, 1H), 7.19 (dd, J=8.6, 2.3Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.82 (s, 1H),6.05-5.78 (m, 1H), 5.68 (dd, J=15.7, 2.8 Hz, 1H), 5.25 (s, 1H),4.22-3.99 (m, 3H), 3.99-3.85 (m, 3H), 3.71 (d, J=14.7 Hz, 2H), 3.38 (dd,J=14.9, 8.9 Hz, 2H), 3.20-2.67 (m, 6H), 2.32-2.15 (m, 8H), 2.04-1.90 (m,3H), 1.83 (dq, J=9.4, 4.9 Hz, 3H), 1.65 (q, J=9.4 Hz, 1H), 1.52-1.23 (m,6H), 1.12 (d, J=6.4 Hz, 3H).

Example 215[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-methoxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using (3R)-3-methoxypyrrolidine to replacemorpholine. LCMS calc. for C₃₈H₅₀ClN₄O₇S [M+H]⁺: m/z=741.33/743.33;Found: 741.5/743.5. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H),7.63-7.45 (m, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H),6.96 (dd, J=8.4, 1.1 Hz, 1H), 6.85 (dd, J=5.4, 2.2 Hz, 1H), 6.00-5.62(m, 2H), 5.40-5.25 (m, 1H), 4.17 (d, J=12.2 Hz, 1H), 4.12-3.94 (m, 2H),3.86 (d, J=13.2 Hz, 1H), 3.72 (d, J=14.7 Hz, 1H), 3.67-3.26 (m, 8H),3.09 (ddd, J=14.7, 11.0, 3.2 Hz, 1H), 2.82 (ddd, J=15.4, 10.3, 5.9 Hz,6H), 2.28 (s, 3H), 1.95 (dddd, J=46.8, 27.6, 9.1, 5.6 Hz, 6H), 1.79-1.54(m, 1H), 1.50-1.23 (m, 6H), 1.11 (s, 3H).

Example 216[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]azetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using azetidine hydrochloride salt and Hunig'sbase to replace morpholine. LCMS calc. for C₃₆H₄₆ClN₄O₆S [M+H]⁺:m/z=697.27/699.27; Found: 697.4/699.5. ¹H NMR (300 MHz, CDCl₃) δ 7.70(d, J=8.5 Hz, 1H), 7.52-7.42 (m, 1H), 7.24-7.05 (m, 2H), 7.01-6.90 (m,1H), 6.86 (s, 1H), 5.92 (s, 1H), 5.72-5.60 (m, 1H), 5.22 (s, 1H),4.39-3.87 (m, 4H), 3.72 (d, J=14.6 Hz, 1H), 3.47 (d, J=15.0 Hz, 1H),3.34 (d, J=14.8 Hz, 1H), 3.15-2.98 (m, 1H), 2.89 (s, 2H), 2.78 (d,J=10.5 Hz, 3H), 2.28 (s, 6H), 1.99 (d, J=12.0 Hz, 2H), 1.84 (d, J=15.0Hz, 4H), 1.65 (q, J=9.5 Hz, 1H), 1.30 (d, J=22.5 Hz, 5H), 1.17-0.98 (m,4H).

Example 217[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-methoxyazetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 Step 2 using 3-methoxyazetidine hydrochloride salt andHunig's base to replace morpholine. LCMS calc. for C₃₇H₄₈ClN₄O₇S [M+H]⁺:m/z=727.29/729.29; Found: 727.4/729.5. ¹H NMR (300 MHz, CDCl₃) δ 7.69(d, J=8.5 Hz, 1H), 7.51 (dd, J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5, 2.4Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 6.82 (d, J=2.2Hz, 1H), 5.86 (s, 1H), 5.67 (d, J=15.9 Hz, 1H), 5.26 (s, 1H), 4.24 (s,3H), 4.18 (d, J=12.2 Hz, 1H), 4.05 (d, J=12.1 Hz, 1H), 3.97 (d, J=7.9Hz, 2H), 3.72 (d, J=14.7 Hz, 1H), 3.37 (d, J=14.7 Hz, 3H), 3.35-3.27 (m,3H), 3.07 (dd, J=15.0, 11.1 Hz, 1H), 2.81 (s, 5H), 2.88-2.73 (m, 1H),2.28 (s, 3H), 2.01 (s, 1H), 1.82 (s, 4H), 1.65 (q, J=9.4 Hz, 1H), 1.37(s, 3H), 1.27 (d, J=4.3 Hz, 1H), 1.11 (s, 3H).

Example 218[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43) in Step 2 and (3R)—N-methyltetrahydrofuran-3-aminehydrochloride in Step 1. LCMS calc. for C₃₈H₅₀ClN₄O₇S [M+H]⁺:m/z=741.30/743.30; Found: 741.4/743.3. ¹H NMR (300 MHz, CDCl₃) δ 7.69(d, J=8.5 Hz, 1H), 7.51 (dd, J=8.4, 2.1 Hz, 1H), 7.19 (dd, J=8.6, 2.4Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.84 (d, J=2.2Hz, 1H), 5.85-5.77 (m, 1H), 5.76-5.67 (m, 1H), 5.36 (s, 1H), 5.00 (s,1H), 4.18 (d, J=12.2 Hz, 1H), 4.10-4.03 (m, 2H), 3.74 (d, J=15.1 Hz,2H), 3.46 (d, J=14.8 Hz, 1H), 3.37 (d, J=14.7 Hz, 1H), 3.15-3.08 (m,1H), 3.06-2.95 (m, 3H), 2.82 (t, J=9.4 Hz, 4H), 2.28 (s, 6H), 1.99 (d,J=11.0 Hz, 2H), 1.90-1.61 (m, 9H), 1.35 (s, 3H), 1.27 (s, 3H).

Example 219(3R,6R,7S,8E,22S)-6′-Chloro-7-hydroxy-11-ethyl-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 27 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43, Step 3) and acetaldehyde. LCMS calc. for C₃₃H₄₃ClN₃O₅S[M+H]⁺: m/z=628.25/630.25; Found: 628.4/630.4. ¹H NMR (600 MHz, DMSO-d₆)δ 7.64 (d, J=8.6 Hz, 1H), 7.25 (dd, J=8.4, 2.4 Hz, 1H), 7.25-7.15 (m,3H), 7.10 (d, J=8.1 Hz, 1H), 6.76 (s, 1H), 5.72 (s, 1H), 5.33 (t, J=5.0Hz, 1H), 4.88-4.84 (m, 1H), 3.99 (t, J=10.4 Hz, 2H), 3.51 (s, 1H), 3.02(s, 2H), 2.80 (d, J=16.8 Hz, 1H), 2.72 (dd, J=11.1, 6.1 Hz, 1H), 2.54(s, 4H), 2.00 (dt, J=19.0, 7.0 Hz, 5H), 1.85 (s, 5H), 1.85-1.81 (m, 1H),1.64 (d, J=8.2 Hz, 2H), 1.56 (s, 1H), 1.46 (p, J=7.2 Hz, 2H), 1.39 (s,2H), 1.30 (s, 2H), 1.15 (s, 1H), 0.86 (t, J=6.8 Hz, 3H).

Example 220[(3R,6R,7S,8E,22S)-6′-Chloro-11-ethyl-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-tetrahydropyran-4-ylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 199 using(3R,6R,7S,8E,22S)-6′-chloro-11-ethyl-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 219) in Step 1 and 4-aminotetrahydropyran in Step 2. LCMScalcd. for C₃₉H₅₂ClN₄O₇S [M+H]⁺: m/z=755.32/757.32; Found: 755.5/757.6.¹H NMR (600 MHz, DMSO-d₆) δ 7.65 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5, 2.4Hz, 1H), 7.19 (dd, J=9.9, 5.1 Hz, 2H), 6.96 (dd, J=14.4, 7.0 Hz, 2H),5.59 (s, 1H), 4.99 (d, J=4.0 Hz, 1H), 4.11 (d, J=12.3 Hz, 1H), 4.05 (d,J=11.6 Hz, 1H), 3.68 (s, 3H), 3.58-3.12 (m, 9H), 2.82-2.76 (m, 1H), 2.72(q, J=8.4 Hz, 2H), 2.65 (s, 7H), 2.43 (s, 1H), 1.98 (dt, J=13.8, 4.6 Hz,1H), 1.83 (h, J=6.0, 4.9 Hz, 3H), 1.71 (q, J=8.6 Hz, 2H), 1.63-1.53 (m,1H), 1.48 (dd, J=14.5, 7.6 Hz, 1H), 1.31 (s, 3H), 1.27-1.21 (m, 2H),1.19 (s, 3H).

Example 221[(3R,6R,7S,8E,22S)-6′-Chloro-11-ethyl-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]morpholine-4-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 using(3R,6R,7S,8E,22S)-6′-chloro-11-ethyl-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 219) in Step 1 and morpholine in Step 2. LCMS calc. forC₃₈H₄₉ClN₄O₇S [M+H]⁺: m/z=741.3/743.37; Found 741.6/741.6. ¹H NMR (300MHz, CDCl₃) δ 7.67 (d, J=8.5 Hz, 1H), 7.59-7.47 (m, 1H), 7.24-7.07 (m,2H), 7.05-6.90 (m, 2H), 5.89 (s, 1H), 5.64 (d, J=16.5 Hz, 1H), 5.36 (s,1H), 4.19 (d, J=12.2 Hz, 1H), 4.06 (d, J=12.0 Hz, 1H), 3.70 (d, J=13.1Hz, 6H), 3.35 (d, J=14.6 Hz, 3H), 3.09 (s, 6H), 2.81 (m, 10H), 2.31 (d,J=9.3 Hz, 1H), 2.07-1.94 (m, 3H), 1.84 (t, J=9.2 Hz, 2H), 1.31 (s, 6H).

Example 222[(3R,6R,7S,8E,22S)-6′-Chloro-11-ethyl-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-methoxypiperidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 using(3R,6R,7S,8E,22S)-6′-chloro-11-ethyl-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 219) in Step 1 and 4-methoxypiperidine in Step 2. LCMS calc.for C₄₀H₅₄ClN₄O₇S [M+H]⁺: m/z=769.34/771.34; Found 769.7/771.8. ¹H NMR(300 MHz, CDCl₃) δ 7.63 (dd, J=19.7, 8.5 Hz, 1H), 7.52 (dd, J=8.3, 2.1Hz, 1H), 7.24-7.06 (m, 3H), 7.00 (d, J=8.4 Hz, 1H), 5.86 (s, 2H), 5.61(s, 1H), 4.19 (d, J=12.1 Hz, 1H), 5.32 (s, 2H), 4.06 (d, J=12.1 Hz, 1H),3.90 (m, 16H), 3.70 (d, J=14.7 Hz, 1H), 3.35 (d, J=16.0 Hz, 7H), 3.11(s, 1H), 1.97 (t, J=10.3 Hz, 1H), 1.80 (dt, J=18.6, 8.5 Hz, 1H),1.67-1.54 (m, 1H), 1.36-1.21 (m, 10H).

Example 223[(3R,6R,7S,8E,22S)-6′-Chloro-11-ethyl-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-(methylamino)azetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 using(3R,6R,7S,8E,22S)-6′-chloro-11-ethyl-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(30.0 mg, Example 219) in Step 1 and tert-butylN-(azetidin-3-yl)-N-methyl-carbamate (74.67 mg, 0.40 mmol) in Step 2.The reaction mixture was concentrated under reduced pressure The residuewas dissolved in IPA (0.50 mL) and DCM (0.50 mL), and treated withphosphoric acid (0.5 mL, 8.6 mmol). The resulting mixture was stirredfor 16 h., and quenched with sat. NaHCO_(3(aq)) (1 mL). The mixture wasextracted with DCM (1 mL×3). The organic layer was concentrated and theresidue was purified by prep-HPLC on a C18 column with MeCN/H₂O (15% to100%) to afford the title compound (6 mg, 20.2% yield). LCMS calc. forC₃₈H₅₁ClN₅O₆S [M+H]⁺: m/z=740.32/742.32; Found 740.5/742.6. ¹H NMR (600MHz, DMSO-d₆) δ 7.64 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5, 2.3 Hz, 1H),7.17 (d, J=2.3 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H),6.72 (s, 1H), 6.41 (t, J=12.5 Hz, 1H), 5.80 (d, J=15.7 Hz, 1H), 5.11 (s,1H), 3.99 (q, J=12.2 Hz, 3H), 3.74-3.65 (m, 2H), 3.56 (d, J=14.5 Hz,1H), 3.31-3.24 (m, 1H), 3.03 (dd, J=15.2, 11.1 Hz, 1H), 2.96 (dd,J=12.6, 6.8 Hz, 1H), 2.83-2.76 (m, 1H), 2.70 (ddd, J=17.2, 11.3, 6.2 Hz,2H), 2.51 (s, 1H), 2.32 (q, J=8.8 Hz, 1H), 2.24 (s, 3H), 1.99 (ddt,J=17.6, 12.2, 5.6 Hz, 2H), 1.93-1.77 (m, 3H), 1.73-1.63 (m, 3H), 1.41(s, 3H), 1.32-1.28 (m, 1H), 1.30-1.18 (m, 10H), 0.86 (t, J=6.9 Hz, 1H).

Example 224[(3R,6R,7S,8E,22S)-6′-Chloro-11-ethyl-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-(dimethylamino)azetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 using(3R,6R,7S,8E,22S)-6′-chloro-11-ethyl-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 219) in Step 1 and N,N-dimethylazetidin-3-amine in Step 2. LCMScalc. for C₃₉H₅₃ClN₅O₆S [M+H]⁺: m/z=754.33/756.43; Found 756.5/758.6. ¹HNMR (300 MHz, CDCl₃) δ 7.70 (d, J=8.5 Hz, 1H), 7.63-7.45 (m, 1H), 7.19(dd, J=8.5, 2.4 Hz, 1H), 7.10 (dd, J=9.3, 2.2 Hz, 1H), 6.94 (d, J=8.4Hz, 1H), 6.80 (s, 1H), 6.18 (s, 1H), 5.69 (d, J=14.6 Hz, 1H), 5.18 (s,1H), 4.38 (s, 1H), 4.16 (d, J=12.3 Hz, 1H), 4.03 (d, J=10.9 Hz, 2H),3.86 (s, 1H), 3.71 (d, J=14.6 Hz, 1H), 3.36 (d, J=14.7 Hz, 1H),3.25-3.09 (m, 1H), 3.01 (m, 15H), 2.79 (m, 4H), 2.20 (d, J=16.2 Hz, 7H),1.98 (d, J=12.3 Hz, 1H), 1.64 (q, J=9.3 Hz, 1H), 1.46 (d, J=30.9 Hz,3H), 1.23 (q, J=7.8, 7.2 Hz, 3H).

Example 225[(3R,6R,7S,8E,22S)-6′-Chloro-11-ethyl-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-(2-methoxyethyl)piperazine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 199 using(3R,6R,7S,8E,22S)-6′-chloro-11-ethyl-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 219) in Step 1 and 1-(2-methoxyethyl)piperazine in Step 2. LCMScalc. for C₄₁H₅₇ClN₅₀₇S [M+H]⁺: m/z=798.36/800.36; Found: 799.1/801.1.

Example 226[(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-[(3S)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43) in Step 2 and (3S)—N-methyltetrahydrofuran-3-aminehydrochloride in Step 1. LCMS calc. for C₃₈H₅₀ClN₄O₇S [M+H]⁺:m/z=741.30/743.30; Found: 741.4/743.3. ¹H NMR (300 MHz, CDCl₃) δ 7.69(d, J=8.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.3 Hz, 1H),7.09 (d, J=2.3 Hz, 1H), 7.03-6.95 (m, 1H), 6.89-6.75 (m, 1H), 5.94-5.62(m, 2H), 5.38 (s, 1H), 4.97 (s, 1H), 4.18 (d, J=12.1 Hz, 1H), 4.13-3.96(m, 2H), 3.90-3.62 (m, 4H), 3.41 (dd, J=25.6, 15.3 Hz, 2H), 3.06 (dd,J=39.0, 17.3 Hz, 4H), 2.81 (t, J=12.5 Hz, 5H), 2.26 (d, J=14.2 Hz, 5H),2.12-1.56 (m, 10H), 1.35 (s, 4H), 1.27 (s, 2H).

Example 227[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-ethylene-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 46 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-ethylene-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.0˜3,6.0˜19,24]pentacosa[8,16(25),17,19(24)]tetraene-22,1′-tetralin]-13-one(Example 40) in Step 1 and methylamine (40% in water) in Step 2. LCMScalc. for C₃₃H₃₉ClN₃O₇S [M+H]⁺: m/z=656.22/658.22; Found: 656.6/658.5.¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.50(dd, J=8.3, 2.0 Hz, 1H), 7.37 (d, J=1.6 Hz, 1H), 7.17 (dd, J=8.5, 2.1Hz, 1H), 7.09 (d, J=2.1 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 5.81-5.56 (m,2H), 5.09 (d, J=6.6 Hz, 1H), 4.46 (s, 1H), 4.14 (s, 2H), 4.07 (dd,J=13.3, 5.2 Hz, 1H), 3.95 (dd, J=13.0, 7.5 Hz, 1H), 3.67 (t, J=10.3 Hz,1H), 3.60 (d, J=7.4 Hz, 1H), 3.30 (d, J=14.6 Hz, 1H), 3.17 (dd, J=15.3,4.7 Hz, 1H), 2.76 (d, J=4.8 Hz, 4H), 2.72-2.61 (m, 1H), 2.56 (dd,J=16.5, 8.3 Hz, 1H), 2.05-1.85 (m, 3H), 1.81 (dd, J=10.7, 7.7 Hz, 1H),1.70 (dd, J=11.7, 7.0 Hz, 2H), 1.62 (d, J=12.4 Hz, 2H), 1.55-1.30 (m,3H), 1.22 (ddd, J=13.3, 11.2, 4.6 Hz, 2H).

Example 228[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-ethoxypyrrolidine-1-carboxylate

Step 1: I-allyloxy-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-cyclobutanecarboxamide

A mixture of(3S)-6′-chloro-5-[[(1R,2R)-2-[1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(3.0 g, 5.96 mmol), 1-allyloxycyclobutanecarboxylic acid (3.26 g, 20.87mmol), DMAP (5.83 g, 47.71 mmol) and EDC (5.72 g, 29.82 mmol) in DCM (30mL) was stirred at 30° C. for 2 h. LCMS showed the conversion of thestarting material into the desired product. The mixture was quenchedwith sat. NH₄Cl(aq) (20 mL) and extracted with DCM (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was dissolved in THF(10 mL), water (10 mL) and methanol (10 mL), and treated with LiOH (1.29g, 30.79 mmol). The mixture was stirred at 30° C. overnight, andquenched with 1M HCl (20 mL). The mixture was extracted with EtOAc (20mL×3). The combined organic layers were washed with sat. NaHCO₃(aq) (20mL) and brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon a silica gel column with EA:Hep (5% to 30%) to afford1-allyloxy-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-cyclobutanecarboxamide(2.35 g, 71.4% yield).

Step 2:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

A solution of1-allyloxy-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-cyclobutanecarboxamide(2.35 g, 3.66 mmol) in DCE (2.5 L) was bubbled with N₂ gas for 15 min.,then Hoveyda-Grubbs 11(0.46 g, 0.73 mmol) was added and the mixture wasbubbled with N₂ gas for an additional 15 min. The mixture was stirredfor 2 h. at 40° C. under N2. LCMS showed the conversion of the startingmaterial into the desired product. The mixture was then exposed to airand stirred for 30 min before it was concentrated under reducedpressure. The reside was purified by flash chromatography on a silicagel column eluting with EA:Hep (10% to 60%) to afford(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(1.49 g, 66.3% yield).

Step 3:[(3R,6R,7S,8E,22S)-6′-chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-ethoxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-onein Step 1 and (3R)-3-ethoxypyrrolidine in Step 2. LCMS calc. forC₃₉H₄₉ClN₃O₈S [M+H]⁺: m/z=754.29/756.29; Found: 754.4/756.4. ¹H NMR (300MHz, CDCl₃) δ 7.70 (dd, J=8.5, 4.3 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.18(d, J=8.4 Hz, 1H), 7.10-6.91 (m, 3H), 5.96 (s, 1H), 5.62 (ddd, J=15.6,9.3, 5.4 Hz, 1H), 5.17 (d, J=4.8 Hz, 1H), 4.08 (m, 4H), 3.76-3.60 (m,3H), 3.59-3.32 (m, 3H), 3.32-3.12 (m, 2H), 2.81-2.63 (m, 2H), 2.44 (m,1H), 2.09 (dd, J=58.7, 11.5 Hz, 7H), 1.82 (t, J=8.0 Hz, 3H), 1.63 (q,J=9.4 Hz, 1H), 1.33-1.18 (m, 9H), 1.09 (dd, J=8.8, 6.3 Hz, 3H).

Example 229[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3S)-3-methoxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 228 Step 2) in Step 1 and (3R)-3-methoxypyrrolidine HCl andDIPEA in Step 2. LCMS calc. for C₃₉H₅₃ClN₅O₆S [M+H]⁺: m/z=740.28/742.27;Found: 740.4/742.5. ¹H NMR (300 MHz, CDCl₃) δ 7.68 (dd, J=8.5, 5.3 Hz,1H), 7.48 (dd, J=8.3, 2.1 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.13-6.99 (m,2H), 6.97 (dd, J=8.3, 2.6 Hz, 1H), 5.80 (d, J=15.9 Hz, 1H), 5.64 (td,J=15.6, 13.8, 5.0 Hz, 1H), 5.23 (s, 1H), 4.23-4.01 (m, 3H), 3.75-3.46(m, 2H), 3.47-3.29 (m, 5H), 3.29-3.08 (m, 1H), 2.78 (s, 3H), 2.67-2.48(m, 1H), 2.42 (d, J=7.4 Hz, 2H), 2.35-2.17 (m, 1H), 2.10 (q, J=10.4, 9.9Hz, 1H), 1.97 (dd, J=14.7, 6.0 Hz, 2H), 1.87 (dd, J=27.0, 5.2 Hz, 2H),1.70-1.40 (m, 2H), 1.29 (d, J=16.4 Hz, 3H), 1.10 (d, J=6.6 Hz, 8H).

Example 230[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]-N,N-1,3-(2-ethoxy)propylenecarbamate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 228 Step 2) in Step 1 and 3-ethoxyazetidine in Step 2. LCMScalc. for C₃₈H₄₇ClN₃O₈S [M+H]⁺: m/z=740.27/742.27; Found:740.4/742.4; ¹HNMR (300 MHz, CDCl₃) δ 7.68 (d, J=8.5 Hz, 1H), 7.45 (dd, J=8.3, 2.0 Hz,1H), 7.16 (dd, J=8.5, 2.4 Hz, 1H), 7.05 (dd, J=13.4, 2.3 Hz, 2H), 6.94(d, J=8.3 Hz, 1H), 5.83 (s, 1H), 5.60 (dd, J=15.7, 5.4 Hz, 1H), 5.12 (s,1H), 4.28-3.98 (m, 7H), 3.67 (m, 3H), 3.48-3.37 (m, 4H), 3.29 (d, J=14.5Hz, 1H), 2.76 (d, J=5.0 Hz, 2H), 2.27-2.16 (m, 3H), 2.10-1.93 (m, 7H),1.80-1.64 (m, 6H), 1.21-1.18 (m, 3H).

Example 231[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15%6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]N,N-dimethyl-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 228 Step 2) in Step 1 and dimethylamine (2.0 M in THF) in Step2. LCMS calc. for C₃₅H₄₃ClN₃O₇S [M+H]⁺: m/z=684.24/686.24; Found:684.3/686.2; ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.45 (dd,J=8.3, 2.0 Hz, 1H), 7.16 (dd, J=8.5, 2.4 Hz, 1H), 7.04 (dd, J=18.7, 2.2Hz, 2H), 6.93 (d, J=8.3 Hz, 1H), 6.10-5.97 (m, 1H), 5.62 (dd, J=15.7,5.8 Hz, 1H), 5.13 (t, J=5.0 Hz, 1H), 4.07 (d, J=3.8 Hz, 1H), 3.99 (dd,J=14.0, 6.3 Hz, 1H), 3.80-3.68 (m, 2H), 3.65 (s, 1H), 3.51 (d, J=14.1Hz, 1H), 3.24 (d, J=14.4 Hz, 1H), 3.14 (dd, J=15.0, 8.8 Hz, 1H),2.94-2.82 (m, 6H), 2.75-2.69 (m, 3H), 2.67 (s, 3H), 2.14-1.92 (m, 6H),1.76-1.66 (m, 6H).

Example 232[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]N,N-1,3-propylene carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 228 Step 2) in Step 1 and azetidine hydrochloride and DIPEA inStep 2. LCMS calc. for C₃₇H₄₅ClN₃O₆S [M+H]⁺: m/z=696.24/698.24; Found:696.3/698.4; ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.15 (dd,J=8.5, 2.3 Hz, 2H), 7.09-7.00 (m, 2H), 6.91 (d, J=8.3 Hz, 1H), 5.63 (dd,J=15.4, 5.8 Hz, 1H), 5.37-5.31 (m, 1H), 5.12 (s, 1H), 4.10-3.88 (m, 7H),3.66-3.64 (m, 2H), 3.24-3.20 (m, 1H), 2.76 (s, 2H), 2.40-2.31 (m, 4H),2.21-2.08 (m, 5H), 2.06-1.93 (m, 6H), 1.76-1.62 (m, 7H).

Example 233[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]N-[2-(dimethylamino)ethyl]-N-methyl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 228 Step 2) in Step 1 and N,N,N′-trimethylethylenediamine inStep 2. LCMS calc. for C₃₈H₅₀ClN₄O₇S [M+H]⁺: m/z=741.30/743.30;Found:741.4/743.3; ¹H NMR (300 MHz, CDCl₃) δ 7.71 (d, J=8.5 Hz, 1H),7.46 (d, J=8.2 Hz, 1H), 7.18 (dd, J=8.5, 2.4 Hz, 2H), 7.09 (s, 1H), 6.94(d, J=8.3 Hz, 1H), 6.41 (s, 1H), 6.07 (s, 1H), 5.66 (d, J=15.0 Hz, 1H),5.34 (d, J=11.5 Hz, 1H), 4.98 (s, 1H), 4.69 (s, 1H), 4.20-4.00 (m, 4H),3.71 (d, J=15.5 Hz, 3H), 3.50 (d, J=14.1 Hz, 2H), 3.37-3.26 (m, 2H),3.03-2.95 (m, 4H), 2.85 (s, 3H), 2.78 (s, 2H), 2.74 (s, 1H), 2.41 (s,3H), 2.23-2.20 (m, 4H), 1.99-1.87 (m, 4H), 1.82-1.75 (m, 4H).

Example 234[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 228 Step 2) in Step 2 and (3R)—N-methyltetrahydrofuran-3-aminehydrochloride in Step 1. LCMS calc. for C₃₈H₄₇ClN₃O₈S [M+H]⁺:m/z=740.27/742.27; Found: 740.4/742.2. ¹H NMR (300 MHz, CDCl₃) δ 7.67(d, J=8.5 Hz, 1H), 7.51 (dd, J=8.3, 2.1 Hz, 1H), 7.18 (dd, J=8.5, 2.4Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 7.00 (d, J=8.3Hz, 1H), 5.66 (d, J=2.8 Hz, 2H), 5.30-5.19 (m, 1H), 4.89 (s, 1H), 4.20(d, J=12.1 Hz, 1H), 4.12 (s, 1H), 4.08 (d, J=3.4 Hz, 1H), 4.01 (dd,J=8.6, 4.8 Hz, 1H), 3.76 (d, J=5.9 Hz, 2H), 3.70 (d, J=7.5 Hz, 1H), 3.66(s, 1H), 3.56 (d, J=13.8 Hz, 1H), 3.38 (s, 1H), 3.32 (d, J=6.5 Hz, 2H),2.86 (s, 3H), 2.79-2.72 (m, 4H), 2.04-1.70 (m, 12H), 1.67-1.49 (m, 4H).

Example 235[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-(oxetan-3-yl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 228 Step 2) in Step 2 and N-methyloxetan-3-amine in Step 1.LCMS calc. for C₃₇H₄₅ClN₃O₈S [M+H]⁺: m/z=726.26/728.26; Found:726.4.4/728.6. ¹H NMR (300 MHz, CDCl₃) δ 7.68 (dq, J=12.6, 8.1 Hz, 2H),7.51 (dd, J=8.3, 2.1 Hz, 1H), 7.18-7.00 (m, 3H), 5.88 (tdd, J=16.8,10.4, 5.5 Hz, 1H), 5.64 (s, 2H), 5.38-5.01 (m, 3H), 4.77 (dt, J=13.4,7.0 Hz, 2H), 4.25-4.02 (m, 3H), 3.97-3.84 (m, 1H), 3.83-3.52 (m, 3H),3.29 (d, J=20.3 Hz, 3H), 3.06 (s, 3H), 2.78 (s, 4H), 2.57-2.05 (m, 3H),2.09-1.77 (m, 2H), 1.60 (dd, J=20.4, 10.9 Hz, 2H), 1.47-1.23 (m, 5H).

Example 236[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-tetrahydropyran-4-yl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 228 Step 2) in Step 2 and N-methyltetrahydropyran-4-amine inStep 1. LCMS calc. for C₃₉H₄₉ClN₃O₈S [M+H]⁺: m/z=754.29/756.29; Found:754.4/756.5. ¹H NMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 7.67 (d, J=8.5 Hz,1H), 7.51 (dd, J=8.4, 2.1 Hz, 1H), 7.21-6.92 (m, 4H), 5.64 (s, 2H), 5.25(s, 1H), 4.25-4.05 (m, 2H), 4.01 (d, J=10.4 Hz, 6H), 3.73 (dd, J=30.6,14.2 Hz, 1H), 3.56 (d, J=13.7 Hz, 1H), 3.48-3.29 (m, 8H), 2.84-2.68 (m,7H), 2.56-2.44 (m, 1H), 2.45-2.20 (m, 1H), 2.24-1.98 (m, 1H), 2.04-1.83(m, 1H), 1.82 (q, J=10.4, 7.9 Hz, 4H), 1.57 (s, 1H), 1.29 (d, J=16.1 Hz,3H).

Example 237[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]N-[(3S)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-12,12-(1,3-propylene)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 228 Step 2) in Step 2 and (3S)-tetrahydrofuran-3-amine inStep 1. LCMS calc. for C₃₇H₄₅ClN₃O₈S [M+H]⁺: m/z=726.26/728/26; Found:726.4/728.4.

Example 238[(3R,6R,7S,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-methoxyazetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 48 Step 8) in Step 1 and 3-methoxyazetidine hydrochloride andDIPEA in Step 2. LCMS calc. for C₃₈H₄₈ClN₄O₇S [M+H]⁺: m/z=739.2/741.2;Found: 739.4/741.5. ¹H NMR (300 MHz, CDCl₃) δ 7.70 (d, J=8.5 Hz, 1H),7.53 (dd, J=8.4, 2.3, 1H), 7.23-7.18 (m, 1H), 7.10 (d, J=2.3 Hz, 1H),7.00 (dd, J=8.3, 1.0 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 5.72-5.67 (m, 2H),5.24 (br, 1H), 4.23-4.06 (m, 4H), 3.96 (d, J=8.3 Hz, 1H), 3.73 (d,J=14.8 Hz, 1H), 3.45-3.40 (m, 2H), 3.33 (s, 3H), 3.12 (dd, J=14.9, 10.6Hz, 1H), 2.89-2.66 (m, 5H), 2.44 (s, 3H), 2.35-2.15 (m, 4H), 2.04-1.92(m, 4H), 1.85-1.64 (m, 7H), 1.34-1.30 (m, 3H).

Example 239[(3R,6R,7S,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-tetrahydropyran-4-yl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 48 Step 8) in Step 2 and N-methyltetrahydropyran-4-amine inStep 1. LCMS calc. for C₄₀H₅₂ClN₄O₇S [M+H]⁺: m/z=767.32/769.32; Found:767.5/769.8. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.5 Hz, 1H), 7.52 (dd,J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.09 (d, J=2.3 Hz,1H), 6.99 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H), 5.72 (s, 2H), 5.33(s, 1H), 4.27 (s, 1H), 4.17 (d, J=12.2 Hz, 1H), 4.06 (d, J=12.2 Hz, 1H),3.73 (d, J=14.7 Hz, 1H), 3.55-3.40 (m, 4H), 3.36 (d, J=14.4 Hz, 1H),3.13 (t, J=12.8 Hz, 1H), 2.90 (d, J=11.8 Hz, 3H), 2.89-2.63 (m, 7H),2.58-2.43 (m, 1H), 2.42 (s, 3H), 2.36-2.05 (m, 1H), 2.01 (s, 2H),2.00-1.84 (m, 1H), 1.85-1.52 (m, 8H), 1.44 (t, J=12.0 Hz, 1H), 1.36-1.20(m, 4H).

Example 240[(3R,6R,7S,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-(oxetan-3-yl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 48 Step 8) in Step 2 and N-methyloxetan-3-amine in Step 1. LCMScalc. for C₃₈H₄₈ClN₄O₇S [M+H]⁺: m/z=739.29/741.29; Found: 739.5/741.5.

Example 241[(3R,6R,7S,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-[(3S)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 48 Step 8) in Step 2 and (3S)—N-methyltetrahydrofuran-3-aminehydrochloride in Step 1. LCMS calc. for C₃₉H₄₉ClN₃O₈S [M+H]⁺:m/z=753.31/755.31; Found: 753.4/755.4. ¹H NMR (300 MHz, Chloroform-d) δ7.69 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.4, 2.1 Hz, 1H), 7.24-7.16 (m, 1H),7.09 (d, J=2.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H),5.72 (d, J=2.7 Hz, 2H), 5.33 (s, 1H), 4.96 (s, 1H), 4.17 (d, J=12.2 Hz,1H), 4.10-3.98 (m, 2H), 3.85-3.67 (m, 5H), 3.50-3.41 (m, 1H), 3.36 (d,J=14.8 Hz, 1H), 3.13 (dd, J=15.0, 10.5 Hz, 1H), 2.94 (d, J=8.5 Hz, 3H),2.79 (q, J=6.1, 5.7 Hz, 4H), 2.72 (s, 2H), 2.43 (s, 3H), 2.08-1.92 (m,7H), 1.85-1.62 (m, 7H), 1.46 (d, J=12.9 Hz, 1H).

Example 242[(3R,6R,7S,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 48 Step 8) in Step 2 and (3R)—N-methyltetrahydrofuran-3-aminehydrochloride in Step 1. LCMS calc. for C₃₉H₅₀ClN₄O₇S [M+H]⁺:m/z=753.31/755.31; Found: 753.4/755.4. ¹H NMR (300 MHz, Chloroform-d) δ7.69 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.4, 2.1 Hz, 1H), 7.19 (dd, J=8.5,2.4 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.86 (d,J=2.3 Hz, 1H), 5.72 (d, J=1.8 Hz, 2H), 5.40-5.29 (m, 1H), 4.97 (s, 1H),4.17 (d, J=12.1 Hz, 1H), 4.06 (d, J=12.1 Hz, 2H), 3.86-3.74 (m, 3H),3.71 (s, 2H), 3.50-3.40 (m, 1H), 3.36 (d, J=14.7 Hz, 1H), 3.12 (dd,J=15.0, 10.6 Hz, 1H), 2.95 (d, J=8.1 Hz, 3H), 2.79 (q, J=5.8, 5.1 Hz,4H), 2.71 (s, 1H), 2.43 (s, 3H), 2.09-1.89 (m, 7H), 1.89-1.76 (m, 4H),1.75-1.61 (m, 4H), 1.46 (d, J=13.0 Hz, 1H).

Example 243[(3R,6R,7S,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[(3R)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 48 Step 8) in Step 2 and (3R)-tetrahydrofuran-3-amine inStep 1. LCMS calc. for C₃₈H₄₈ClN₄O₇S [M+H]⁺: m/z=739.29/741.29; Found:739.3/741.3.

Example 244[(3R,6R,7S,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-ethoxyazetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 48 Step 8) in Step 1 and 3-ethoxyazetidine; hydrochloride andDIPEA in Step 2. LCMS calc. for C₃₉H₅₀ClN₄O₇S [M+H]⁺: m/z=753.30/755.30;Found: 753.6/755.3. ¹H NMR (300 MHz, CDCl₃) δ 7.70 (d, J=8.5 Hz, 1H),7.52 (dd, J=8.4, 2.0 Hz, 1H), 7.20 (dd, J=8.5, 2.4 Hz, 1H), 7.10 (d,J=2.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 5.72-5.66(m, 2H), 5.24 (br, 1H), 4.22-4.13 (m, 6H), 3.73 (d, J=14.7 Hz, 1H),3.48-3.33 (m, 4H), 3.12 (dd, J=15.0, 10.5 Hz, 1H), 2.84-2.71 (m, 4H),2.44 (s, 3H), 2.32-2.27 (m, 3H), 2.06-1.95 (m, 4H), 1.85-1.80 (m, 3H),1.67-1.61 (m, 2H), 1.45 (t, J=11.8 Hz, 1H), 1.27-1.16 (m, 8H).

Example 245[(3R,6R,7S,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]4-methoxypiperidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 48 Step 8) in Step 1 and 4-methoxypiperidine in Step 2. LC-MS:calc. for C₄₀H₅₂ClN₄O₇S [M+H]⁺: m/z=767.32/769.32; Found 767.4/769.4.

Example 246(3R,6R,7S,8E,22S)-7′-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one

This compound was prepared using procedures analogous to those describedfor Example 32 Step 1-3 using(3S)-7′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,4′-chromane]-7-sulfonamide(Intermediate 12) and 2-allyloxy-2-methyl-propanoic acid (Example 30Step 1). LC-MS: calc. for C₃₀H₃₆ClN₂O₇S [M+H]⁺: m/z=603.2/605.2; Found:603.2/605.2. HPLC: C18 column (4.6×150 mm, 100 Å); flow rate=1 mL/min;mobile phase: 5% MeCN/H₂O (with 0.1% TFA) 2 min, 5% to 95% 6 min, 95% 2min. λ=220 nm. tR=6.813 min. ¹H NMR (499 MHz, DMSO-d₆) δ 11.71 (s, 1H),7.55 (d, J=8.5 Hz, 1H), 7.38-7.20 (m, 1H), 7.15-7.00 (m, 2H), 6.97 (dd,J=8.5, 2.3 Hz, 1H), 6.89 (t, J=2.4 Hz, 1H), 5.67-5.37 (m, 2H), 4.69 (d,J=4.1 Hz, 1H), 4.33-4.17 (m, 3H), 4.05 (d, J=12.1 Hz, 1H), 3.97-3.82 (m,2H), 3.59 (d, J=14.5 Hz, 1H), 3.45 (t, J=15.4 Hz, 2H), 3.17 (dd, J=14.5,7.4 Hz, 1H), 2.60 (q, J=7.8, 6.0 Hz, 1H), 2.34-2.20 (m, 1H), 2.17-1.95(m, 2H), 1.84 (tdt, J=25.5, 16.6, 7.4 Hz, 3H), 1.73-1.51 (m, 2H), 1.36(s, 3H), 1.23 (s, 3H).

Example 247[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]N,N-dimethylcarbamate

To a stirred solution of(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(22.0 mg, 0.04 mmol, Example 246) in MeCN (10 ml) was added CDI (18.11mg, 0.11 mmol). The mixture was stirred at 45° C. for 2 h. LCMS analysisindicated the starting material was fully consumed. Dimethylamine in THF(35 uL, 0.07 mmol, 2.0 N) was added. The reaction mixture was stirred at45° C. for 2 h. HCl (1.0 M, 2 mL) was added. The mixture was extractedwith DCM (5 mL×3). The combined organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC on a C18 column to afford[(3R,6R,7S,8E,22S)-7′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]N,N-dimethylcarbamate (5.8 mg, 23.6% yield) as a white solid. LCMS calc.for C₃₃H₄₁ClN₃₀₈S [M−H]*: m/z=674.2/676.2; Found: 674.4/676.4. ¹H NMR(499 MHz, DMSO-d₆) δ 11.69 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.33-7.18(m, 1H), 7.05-6.94 (m, 3H), 6.88 (d, J=2.2 Hz, 1H), 5.66 (s, 2H), 5.10(t, J=3.5 Hz, 1H), 4.35-4.15 (m, 3H), 4.07 (d, J=12.1 Hz, 1H), 3.94 (d,J=13.7 Hz, 1H), 3.63 (d, J=14.5 Hz, 1H), 3.41 (d, J=14.5 Hz, 1H), 3.25(d, J=6.7 Hz, 2H), 2.92 (s, 3H), 2.83 (s, 3H), 2.69 (q, J=7.9 Hz, 1H),2.43 (s, 1H), 2.11-1.97 (m, 1H), 1.89-1.79 (m, 2H), 1.77-1.60 (m, 3H),1.37 (s, 3H), 1.21 (s, 3H).

Example 248[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]morpholine-4-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 1 and morpholine in Step 2. LC-MS: calc. forC₃₅H₄₃ClN₃O₉S [M+H]⁺: m/z=716.2/718.2; Found: 716.3/718.3. ¹H NMR (300MHz, CDCl₃) δ 7.78 (d, J=7.5 Hz, 1H), 7.57 (dd, J=8.4, 1.1 Hz, 1H), 7.39(d, J=7.6 Hz, 1H), 7.13-7.01 (m, 2H), 6.94 (ddd, J=8.4, 2.3, 1.2 Hz,1H), 5.97-5.64 (m, 2H), 5.34 (t, J=4.3 Hz, 1H), 4.57 (td, J=11.5, 10.4,6.4 Hz, 1H), 4.40-3.94 (m, 5H), 3.80-3.62 (m, 4H), 3.54-3.26 (m, 4H),3.03-2.87 (m, 1H), 2.80 (d, J=7.1 Hz, 3H), 2.08-1.80 (m, 6H), 1.65 (dd,J=12.2, 6.6 Hz, 2H), 1.46 (s, 3H), 1.37 (s, 3H).

Example 249(3R,6R,7S,8E,22R)-6′-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-isochromane]-13-one

This compound was prepared using procedures analogous to those describedfor Example 32 Step 1-3 using(3R)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-isochromane]-7-sulfonamide(Intermediate 15) and 2-allyloxy-2-methyl-propanoic acid (Example 30Step 1). LC-MS: calc. for C₃₀H₃₆ClN₂O₇S [M+H]⁺: m/z=603.2/605.2; Found:603.2/605.2. ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.45 (m, 2H), 7.25-7.14 (m,3H), 7.02 (dd, J=8.4, 1.4 Hz, 1H), 5.86-5.51 (m, 2H), 4.38-4.29 (m, 1H),4.17 (d, J=12.1 Hz, 2H), 4.09-3.96 (m, 2H), 3.84-3.52 (m, 6H), 3.28 (dd,J=14.8, 7.3 Hz, 1H), 2.94 (ddt, J=24.3, 16.0, 7.8 Hz, 2H), 2.80-2.68 (m,1H), 2.40 (q, J=9.1 Hz, 1H), 2.14-1.78 (m, 4H), 1.42 (s, 3H), 1.39 (s,3H).

Example 250[(3R,6R,7S,8E,22R)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-isochromane]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22R)-6′-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-isochromane]-13-one(Example 249) in Step 1 and dimethylamine in THF solution (2.0 N) inStep 2. LC-MS: calc. for C₃₃H₄₁ClN₃O₈S [M+H]⁺: m/z=674.2/676.2; Found:674.3/676.3. ¹H NMR (300 MHz, CDCl₃) δ 7.50 (d, J=8.5 Hz, 1H), 7.43 (dd,J=8.3, 2.0 Hz, 1H), 7.27-7.21 (m, 1H), 7.16 (d, J=2.2 Hz, 1H), 7.10 (d,J=2.2 Hz, 1H), 6.94 (dd, J=8.3, 0.9 Hz, 1H), 6.09 (ddd, J=15.8, 6.4, 4.1Hz, 1H), 5.69 (dd, J=15.7, 5.5 Hz, 1H), 5.25 (t, J=4.2 Hz, 1H), 4.31 (d,J=11.8 Hz, 1H), 4.13 (d, J=11.8 Hz, 1H), 4.02-3.95 (m, 2H), 3.80-3.71(m, 1H), 3.66 (d, J=11.6 Hz, 2H), 3.50-3.38 (m, 2H), 3.03 (s, 3H), 2.95(s, 3H), 2.72 (s, 5H), 2.37 (qd, J=9.0, 2.9 Hz, 1H), 2.04 (qt, J=7.5,3.0 Hz, 1H), 1.84 (q, J=9.0 Hz, 2H), 1.71-1.57 (m, 1H), 1.40 (s, 3H),1.33 (s, 3H).

Example 251 MethylN-[(3R,6R,7R,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

Step 1:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(E)-[(S)-tert-butylsulfinyl]iminomethyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(1000.0 mg, 1.4 mmol, Intermediate 3 Step 3) in DCM (20 mL) was addedcopper sulfate (669.41 mg, 4.19 mmol) followed by the addition of(S)-2-methylpropane-2-sulfinamide (254.16 mg, 2.1 mmol). The reactionmixture was stirred at r.t. overnight. The reaction was filtered througha pad of Celite and washed with DCM. The filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column EtOAc/Hep (3% to 60%) to afford(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(E)-[(S)-tert-butylsulfinyl]iminomethyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(980 mg, 85.6% yield). LCMS calcd. for C₄₄H₅₃ClN₃O₆S₂ [M+H]⁺:m/z=818.31/820.30; Found: 819.0/821.0.

Step 2:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-[[(S)-tert-butylsulfinyl]amino]allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamideand(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-[[(S)-tert-butylsulfinyl]amino]allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a cooled (−78° C.) solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(E)-[(S)-tert-butylsulfinyl]iminomethyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(980.0 mg, 1.2 mmol) in THF (20 mL) was added dropwise vinylmagnesiumbromide (1.8 mL, 1.8 mmol, 1.OM THF solution) over 10 min. Afteraddition, the reaction mixture was allowed to warm to r.t. over 1 h.LCMS showed full conversion of starting material and the formation ofdesired product. The reaction was quenched with sat. NH₄Cl(aq) (20 mL)and extracted with EtOAc (20 mL×3). The organic layer was dried overNaSO₄, filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column EA:Hep (3% to100%) to afford two products: P1 (the earlier eluted product, 410 mg,40.4%) which was assigned to(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-[[(S)-tert-butylsulfinyl]amino]allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamideand P2 (the latter eluted product, 190 mg, 18.7%) which was assigned to(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-[[(S)-tert-butylsulfinyl]amino]allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide.LCMS calcd. for C₄₆H₅₇ClN₃O₆S₂ [M+H]⁺: m/z=846.34/848.33; Found:847.1/849.2.

Step 3:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-aminoallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-[[(S)-tert-butylsulfinyl]amino]allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(400.0 mg, 0.47 mmol, P1 Step 2) in 1,4-dioxane (10 mL) was treated with6 M HCl in IPA solution (1.5 mL, 9.45 mmol). The reaction mixture wasstirred for 1 h. LCMS showed full consume of starting material. Thereaction was quenched with sat. NaHCO_(3(aq)) (10 mL) and extracted withEtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-aminoallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(312 mg, 88.9% yield) which was used in the next step without furtherpurification. LCMS calc. for C₄₂H₄₈ClN₃O₅S [M+H]⁺: m/z=742.31/744.31;Found: 742.7/744.1.

Step 4:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-aminoallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1R)-1-aminoallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(312.0 mg, 0.42 mmol) in DCM (5 mL) was added methyl chloroformate (0.05mL, 0.63 mmol) and triethylamine (0.09 mL, 0.67 mmol). The mixture wasstirred for 4 h. The reaction was quenched with MeOH (1 mL) andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column EtOAc/Heptanes (3% to 50%) toafford methyl N-[(1R)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate (252 mg, 74.9% yield). LCMS calc. for C₄₄H₅₁ClN₃O₇S [M+H]⁺:m/z=800.31/802.31; Found: 800.8/803.0.

Step 5: methylN-[(1R)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate

Methyl N-[(1R)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl) methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate (180.0 mg, 0.22 mmol) was dissolved in2,2,2-trifluoroacetic acid (2.0 mL, 25.96 mmol) and DCM (8 mL). Themixture was stirred at r.t. overnight 16 h. The mixture was quenched bysat. NaHCO₃(a_(q)) (10 mL) and extracted with EtOAc (10 mL×3). Thecombined organic layers were concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columnEtOAc/Heptanes (10% to 50%) to afford methylN-[(1R)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate(116 mg, 92.1% yield). LCMS calc. for C₂₈H₃₅ClN₃O₅S [M+H]⁺:m/z=560.20/562.20; Found: 560.8/562.7.

Step 6: methylN-[(1R)-1-[(1R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propanoyl)sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate

To a solution of methylN-[(1R)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate(48.0 mg, 0.09 mmol) and 2-allyloxy-2-methyl-propanoic acid (24.71 mg,0.17 mmol, Example 30 Step 1) in DCM (2 mL) was added sequentially DMAP(41.88 mg, 0.34 mmol), and EDCI (32.86 mg, 0.17 mmol). The mixture wasstirred at r.t. overnight. The mixture was diluted with DCM (1 mL) andwashed with 1 M HCl(aq) (1 mL). The organic layer was concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column EtOAc/Heptanes (10% to 50%) to afford methylN-[(1R)-1-[(1R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propanoyl)sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate (51 mg, 86.7% yield). LCMS calc. forC₃₅H₄₆ClN₄O₆S [M+H]⁺: m/z=685.28/687.28; Found: 685.8/687.2.

Step 7: methylN-[(3R,6R,7R,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

A solution of methylN-[(1R)-1-[(1R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propanoyl)sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate(51.07 mg, 0.07 mmol) in DCE (60 mL) was bubbled with N₂ gas for 10min., then Hoveyda-Grubbs II (9.33 mg, 0.01 mmol) was added. Thereaction mixture was re-bubbled with N₂ for an additional 10 min. Themixture was then stirred at 40° C. under N₂ overnight. The reaction wasexposed to air for 30 min. before concentrated under reduced pressure.The residue was purified by flash chromatography on a silica gel columnEA:Hep (5% to 60%), and further purified by prep-HPLC H₂O:MeCN (10% to100%) to afford methylN-[(3R,6R,7R,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate(9 mg, 18.4% yield). LCMS calc. for C₃₃H₄₁ClN₃O₇S [M+H]⁺:m/z=658.24/660.23; Found: 658.68/660.8. HPLC: C18 column (4.6×150 mm, 5m); flow rate=1 mL/min; mobile phase: MeCN/H₂O (with 0.1% TFA) 50% to95% 6 min, 95% 4 min; λ=220 nm. tR=6.741 min. ¹H NMR (300 MHz, CDCl₃) δ7.68 (d, J=8.5 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.09-6.98 (m, 4H), 5.62(dd, J=15.4, 7.2 Hz, 1H), 4.11-3.92 (m, 3H), 3.81-3.72 (m, 5H), 3.54 (d,J=14.6 Hz, 1H), 3.33 (d, J=14.5 Hz, 1H), 3.16 (t, J=12.2 Hz, 1H), 2.79(s, 2H), 2.57 (s, 1H), 2.22 (q, J=6.8, 6.0 Hz, 1H), 2.04-1.89 (m, 4H),1.65 (s, 3H), 1.50-1.23 (m, 7H), 0.89 (t, J=6.5 Hz, 1H).

Example 252 MethylN-[(3R,6R,7R,8E,22S)-6′-Chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

Step 1: ethylN-[(1R)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 251 Step 4 using ethyl chloroformate to replace methylchloroformate. LCMS calc. for C₄₅H₅₃ClN₃O₇S [M+H]⁺: m/z=814.33/816.33;Found: 815.0/816.9.

Step 2: ethylN-methyl-N—[(R)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate

To a solution of ethylN-[(1R)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate (371.0 mg, 0.46 mmol) in DMF (6 mL)was added sodium hydride (60% o, dispersion in paraffin liquid) (54.66mg, 1.37 mmol), followed by iodomethane (0.11 mL, 1.82 mmol). Thereaction was stirred at r.t. for 4 h. The reaction was quenched withsat. NH₄Cl (aq) and extracted with EtOAc (10 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford the crude product which was used in the next stepwithout further purification. LCMS calc. for C₄₆H₅₅ClN₃O₇S [M+H]⁺:m/z=828.34/830.33; Found: 828.8/830.2.

Step 3: methylN-[(3R,6R,7R,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 251 Step 5-7 using ethylN-methyl-N-[(1R)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamatein Step 5 and 2-allyloxy-2-methyl-propanoic acid (Example 30 Step 1) inStep 6. LCMS calcd. for C₃₅H₄₅ClN₃O₇S (M+H)⁺: m/z=686.27/688.26; Found:686.3/688.3. HPLC: C18 column (4.6×150 mm, 5 m); flow rate=1 mL/min;mobile phase: MeCN/H₂O (with 0.1% TFA) 50% to 95% 6 min, 95% 4 min;λ=220 nm. tR=8.004 min.

Example 253 EthylN-methyl-N-[(3R,6R,7R,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

Step 1: ethylN-methyl-N-[(3R,6R,7R,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 251 Step 5-7 using ethylN-methyl-N-[(1R)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]carbamate(Example 252, Step 2) in Step 5 and3-allyl-4,4-dimethyl-oxazolidine-2,5-dione (Example 43 Step 1) in Step6. LCMS calcd. for C₃₅H₄₆ClN₄O₆S (M+H)⁺: m/z=685.27/686.26; Found:685.3/687.3.

Step 2: ethylN-methyl-N-[(3R,6R,7R,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 138 Step 3 using ethylN-methyl-N-[(3R,6R,7R,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate andformaldehyde aqueous solution (37%). LCMS calcd. for C₃₆H₄₈ClN₄O₆S[M+H]⁺: m/z=699.30/701.30; Found: 699.4/701.5.

Example 254 MethylN-methyl-N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

Step 1:(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-aminoallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

This compound was prepared using procedures analogous to those describedfor Example 251 Step 3 using(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-[(1S)-1-[[(S)-tert-butylsulfinyl]amino]allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(P2 Example 251 Step 2). LCMS calc. for C₄₂H₄₈ClN₃O₅S [M+H]⁺:m/z=742.31/744.31; Found: 742.7/744.1.

Step 2:2,2,2-trifluoro-N-[(1S)-1-[(R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetamide

To a solution of2,2,2-trifluoro-N-[(1S)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetamide(0.82 g, 1.1 mmol) in DCM (10 mL) was added trifluoroacetic anhydride(0.28 mL, 2.21 mmol) and triethylamine (0.62 mL, 4.42 mmol). The mixturewas stirred for 16 h. The reaction was concentrated under reducedpressure to afford2,2,2-trifluoro-N-[(1S)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetamide(1.6 g) which was used in the next step without further purification.LCMS calc. for C₄₄H₄₈ClF₃N₃O₆S [M+H]⁺: m/z=838.29/840.29; Found:838.8/840.0.

Step 3:2,2,2-trifluoro-N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]acetamide

This compound was prepared using procedures analogous to those describedfor Example 251 Step 5-7 using2,2,2-trifluoro-N-[(1S)-1-[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]acetamidein Step 5 and 2-allyloxy-2-methyl-propanoic acid (Example 30 Step 1) inStep 6. LCMS calc. for C₃₃H₃₈ClF₃N₃O₆S [M+H]⁺: m/z=696.21/698.21; Found:696.3/698.3.

Step 4:(3R,6R,7S,8E,22S)-7-amino-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one

To a solution of2,2,2-trifluoro-N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]acetamide(134.0 mg, 0.19 mmol) in methanol (10 mL) and water (5 mL) was addedpotassium carbonate (265.62 mg, 1.92 mmol). The mixture was stirred at50° C. overnight. The mixture was quenched with NH₄Cl(aq) (10 mL) andextracted with EtOAc (10 mL×3). The combined organic layers wereconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column EA:Hep (10% to 100%) to afford(3R,6R,7S,8E,22S)-7-amino-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(120 mg). LCMS calc. for C₃₁H₃₉ClN₃O₅S [M+H]⁺: m/z=600.22/602.22; Found:600.5/602.5.

Step 5: methylN-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 251 Step 4 using(3R,6R,7S,8E,22S)-7-amino-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-oneand methyl chloroformate. LCMS calc. for C₃₃H₄₀ClN₃O₇S [M+H]⁺:m/z=658.23/660.22; Found: 658.4/660.4.

Step 6: methylN-methyl-N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 252 Step 2 using methylN-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]carbamate andiodomethane. LCMS calc. for C₃₄H₄₃ClN₃O₇S [M+H]⁺: m/z=672.25/674.25;Found: 672.4/674.4; HPLC: C18 column (4.6×150 mm, 5 m); flow rate=1mL/min; mobile phase: MeCN/H₂O (with 0.1% TFA) 50% to 95% 6 min, 95% 4min; λ=220 nm. tR=7.321 min. ¹H NMR (600 MHz, DMSO-d₆) δ 7.65 (d, J=8.5Hz, 1H), 7.30 (s, 1H), 7.23-7.18 (m, 2H), 7.09 (s, 1H), 6.85 (s, 1H),6.66 (s, 1H), 5.63 (s, 1H), 5.33 (t, J=4.9 Hz, 1H), 4.17 (s, 1H), 3.96(d, J=12.7 Hz, 1H), 3.89 (s, 1H), 3.70 (s, 1H), 3.52 (s, 3H), 2.80-2.70(m, 1H), 2.65 (s, 2H), 2.00 (tt, J=13.1, 5.7 Hz, 3H), 1.86 (s, 2H), 1.80(s, 3H), 1.54 (d, J=9.6 Hz, 1H), 1.46 (t, J=7.1 Hz, 2H), 1.29 (d, J=6.4Hz, 1H), 1.26-1.19 (m, 4H), 1.14 (d, J=10.6 Hz, 3H), 0.86 (t, J=6.8 Hz,3H).

Example 255N-Methyl-N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]acetamide

Step 1:N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]acetamide

This compound was prepared using procedures analogous to those describedfor Example 251 Step 4 using(3R,6R,7S,8E,22S)-7-amino-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 254 Step 4) and acetyl chloride. LCMS calcd. for C₃₃H₄₁ClN₃O₆S[M+H]⁺: m/z=642.24/644.24; Found: 642.4/642.3.

Step 2:N-methyl-N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]acetamide

This compound was prepared using procedures analogous to those describedfor Example 252 Step 2 usingN-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]acetamideand iodomethane. LCMS calcd. for C₃₄H₄₃ClN₃O₆S (M+H)⁺:m/z=656.26/658.25; Found: 656.4/658.5. ¹H NMR (600 MHz, CDCl₃) δ7.75-7.70 (m, 1H), 7.60-7.38 (m, 1H), 7.16 (dd, J=8.7, 2.4 Hz, 1H),7.13-7.06 (m, 2H), 7.02 (s, 1H), 6.91 (s, 1H), 5.82 (s, 1H), 5.39 (s,1H), 5.25 (s, 1H), 5.03 (s, 1H), 4.18 (d, J=13.7 Hz, 2H), 4.07 (s, 3H),3.94 (dd, J=13.6, 8.5 Hz, 1H), 3.70 (s, 2H), 3.23 (d, J=14.3 Hz, 1H),2.79 (d, J=5.9 Hz, 1H), 2.78-2.69 (m, 4H), 2.52-2.32 (m, 1H), 2.24-2.19(m, 3H), 2.06-1.94 (m, 4H), 1.92-1.87 (m, 1H), 1.86-1.81 (m, 4H), 1.45(d, J=9.8 Hz, 2H), 0.87 (h, J=7.5, 6.5 Hz, 3H).

Example 256N-Methyl-N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]methanesulfonamide

Step 1:N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]methanesulfonamide

This compound was prepared using procedures analogous to those describedfor Example 251 Step 4 using(3R,6R,7S,8E,22S)-7-amino-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 254 Step 4) and methanesulfonyl chloride. LCMS calcd. forC₃₂H₄₁ClN₃O₇S₂ (M+H)⁺: m/z=678.21/680.20; found: 678.4/660.1.

Step 2:N-methyl-N-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]methanesulfonamide

This compound was prepared using procedures analogous to those describedfor Example 252 Step 2 usingN-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]methanesulfonamideand iodomethane. LCMS calcd. for C₃₃H₄₃ClN₃O₇S₂ [M+H]⁺:m/z=692.22/692.42; found: 692.7/694.7. ¹H NMR (300 MHz, CDCl₃) δ 8.81(s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.21-6.91 (m,4H), 5.84 (dd, J=15.3, 8.7 Hz, 1H), 5.33 (s, 1H), 4.17 (s, 3H), 3.95 (s,2H), 3.69-3.52 (m, 3H), 3.37 (d, J=14.4 Hz, 1H), 3.23 (s, 1H), 2.75 (m,8H), 2.37-1.61 (m, 5H), 1.45 (d, J=12.0 Hz, 6H), 1.36-1.23 (m, 3H).

Example 2571,1,3-Trimethyl-3-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]urea

Step 1:1,1-dimethyl-3-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]urea

This compound was prepared using procedures analogous to those describedfor Example 251 Step 4 using(3R,6R,7S,8E,22S)-7-amino-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 254 Step 4) and N,N-dimethylcarbamoyl chloride. LCMS calcd. forC₃₄H₄₄ClN₄O₆S (M+H)⁺: m/z=671.27/673.26; found: 671.5/673.4.

Step 2:1,1,3-trimethyl-3-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]urea

This compound was prepared using procedures analogous to those describedfor Example 252 Step 2 using1,1-dimethyl-3-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]urea andiodomethane. LCMS calcd. for C₃₅H₄₆ClN₄O₆S [M+H]⁺: m/z=685.28/687.28;found: 685.7/687.7. ¹H NMR (500 MHz, CDCl₃) δ 9.07 (s, 1H), 7.67-7.55(m, 2H), 7.18-7.10 (m, 1H), 7.03 (s, 2H), 6.84 (d, J=8.4 Hz, 1H), 5.89(d, J=10.0 Hz, 1H), 5.56 (d, J=15.1 Hz, 1H), 5.42 (s, 1H), 4.14 (d,J=10.7 Hz, 3H), 4.06 (d, J=11.8 Hz, 1H), 4.01-3.89 (m, 3H), 3.86 (d,J=12.9 Hz, 2H), 3.47 (d, J=15.2 Hz, 2H), 3.26 (d, J=19.2 Hz, 2H), 2.98(d, J=14.6 Hz, 1H), 2.66 (s, 2H), 2.58 (s, 3H), 2.37 (d, J=8.4 Hz, 1H),2.13 (s, 1H), 2.06-1.99 (m, 2H), 1.85 (s, 3H), 1.44 (d, J=14.9 Hz, 4H),1.31 (s, 6H).

Example 258(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(3,3-difluoroazetidin-1-yl)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using 3,3-difluoroazetidine hydrochloride to replacedimethylamine in THF (2.0 M) in Step 5. LCMS calc. for C₃₆H₄₅ClN₃O₆S[M+H]⁺: m/z=720.26/722.26; Found: 720.5/722.6.

Example 259(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-7-[2-(4-methylpiperazin-1-yl)ethoxy]-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using methylpiperazine to replace dimethylamine in THF(2.0 M) in Step 5. LCMS calc. for C₃₈H₅₂ClN₄O₆S [M+H]⁺:m/z=727.32/729.32; Found: 727.5/729.7; ¹H NMR (600 MHz, DMSO-d₆) δ7.63-7.59 (m, 1H), 7.30 (dd, J=8.3, 2.1 Hz, 1H), 7.24 (dd, J=8.5, 2.3Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.07-7.04 (m, 2H), 5.56 (dd, J=15.7,7.2 Hz, 1H), 5.36 (s, 1H), 4.07 (dt, J=27.4, 13.7 Hz, 3H), 3.91-3.85 (m,2H), 3.32 (m, 6H), 3.15 (m, 3H), 2.80-2.76 (m, 2H), 2.74 (s, 4H), 2.65(dd, J=3.9, 1.9 Hz, 1H), 2.47-2.38 (m, 2H), 2.34-2.23 (m, 1H), 2.04-1.93(m, 3H), 1.91-1.76 (m, 5H), 1.74-1.69 (m, 1H), 1.61-1.55 (m, 2H), 1.47(d, J=6.6 Hz, 1H), 1.38 (s, 3H), 1.26 (s, 3H).

Example 260(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-[(3R)-3-methoxypyrrolidin-1-yl]ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using (R)-3-methoxypyrrolidine to replace dimethylaminein THF (2.0 M) in Step 5. LCMS calc. for C₃₈H₅₁ClN₃O₇S [M+H]⁺:m/z=728.31/730.30; Found: 728.5/730.7; ¹H NMR (300 MHz, DMSO-d₆) δ 9.95(s, 1H, NH), 7.61 (d, J=8.5 Hz, 1H), 7.32-7.17 (m, 3H), 7.03 (t, J=7.7Hz, 2H), 5.57 (dd, J=15.7, 6.8 Hz, 1H), 5.46-5.31 (m, 1H), 4.08 (m, 3H),3.87 (dd, J=14.2, 5.8 Hz, 1H), 3.68-3.58 (m, 3H), 3.32 (m, 6H), 3.23 (m,4H), 3.20-3.08 (m, 4H), 2.79-2.62 (m, 3H), 2.28-2.18 (m, 1H), 1.96 (dd,J=18.5, 9.0 Hz, 2H), 1.84 (s, 4H), 1.77-1.61 (m, 2H), 1.58 (d, J=8.2 Hz,2H), 1.37 (s, 3H), 1.24 (s, 3H).

Example 261(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(3-methoxyazetidin-1-yl)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using -methoxyazetidine hydrochloride to replacedimethylamine in THF (2.0 M) in Step 5. LCMS calc. for C₃₇H₄₉ClN₃O₇S[M+H]⁺: m/z=714.29/716.29; Found: 714.5/716.7; ¹H NMR (300 MHz, DMSO-d₆)δ 7.61 (d, J=8.5 Hz, 1H), 7.31-7.15 (m, 3H), 7.02 (dd, J=9.3, 5.7 Hz,2H), 5.56 (dd, J=15.6, 6.1 Hz, 1H), 5.48 (s, 1H), 4.36 (s, 1H),4.27-4.13 (m, 2H), 4.11-4.02 (m, 2H), 3.90 (m, 2H), 3.63 (s, 1H), 3.53(d, J=8.2 Hz, 2H), 3.32 (m, 5H), 3.22 (d, J=7.3 Hz, 4H), 3.19-3.09 (m,2H), 2.76 (dd, J=21.0, 12.7 Hz, 2H), 2.66 (s, 1H), 2.41 (s, 2H), 1.96(d, J=13.3 Hz, 1H), 1.84 (d, J=4.1 Hz, 4H), 1.71 (d, J=8.3 Hz, 1H), 1.55(d, J=7.0 Hz, 2H), 1.37 (s, 3H), 1.24 (s, 3H).

Example 262(3R,6R,7S,8E,22S)-7-[2-(Azetidin-1-yl)ethoxy]-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using azetidine hydrochloride to replace dimethylamine inTHF (2.0 M) in Step 5. LCMS calc. for C₃₇H₄₇ClN₃O₆S [M+H]⁺:m/z=684.28/686.28; Found: 684.4/686.2; ¹H NMR (300 MHz, CDCl₃) δ 10.60(s, 1H, NH), 7.68 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.0 Hz, 1H), 7.18(dd, J=8.5, 2.0 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.01-6.96 (m, 1H), 6.87(t, J=4.3 Hz, 1H), 6.01 (dd, J=15.7, 3.9 Hz, 1H), 5.70 (dd, J=15.6, 5.4Hz, 1H), 4.14-3.94 (m, 5H), 3.76 (dd, J=14.2, 5.2 Hz, 3H), 3.57-3.45 (m,3H), 3.38 (d, J=14.9 Hz, 3H), 3.11 (dd, J=15.0, 11.0 Hz, 2H), 2.76 (M,4H), 2.28 (d, J=7.5 Hz, 1H), 2.23-2.05 (m, 2H), 2.00 (dd, J=14.1, 5.9Hz, 4H), 1.81 (dd, J=16.2, 8.1 Hz, 2H), 1.73-1.58 (m, 2H), 1.50 (d,J=10.2 Hz, 3H), 1.34 (s, 3H).

Example 263(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-15,15-dioxo-7-[2-(1-piperidyl)ethoxy]spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using piperidine to replace dimethylamine in THF (2.0 M)in Step 5. LCMS calc. for C₃₇H₅₁ClN₃O₆S [M+H]⁺: m/z=712.31/714.31;Found: 712.4/714.3; ¹H NMR (300 MHz, CDCl₃) δ 9.53 (s, 1H, NH), 7.67 (d,J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.0 Hz, 1H), 7.18 (dd, J=8.5, 2.1 Hz,1H), 7.10 (d, J=2.0 Hz, 1H), 7.02-6.98 (m, 1H), 6.94 (t, J=3.4 Hz, 1H),5.89 (dd, J=15.6, 3.3 Hz, 1H), 5.64 (dd, J=15.6, 6.1 Hz, 1H), 4.12 (d,J=5.8 Hz, 2H), 4.03 (dd, J=13.0, 5.2 Hz, 2H), 3.71 (d, J=15.0 Hz, 6H),3.36 (d, J=14.5 Hz, 4H), 3.18 (dd, J=15.1, 9.6 Hz, 1H), 2.79 (d, J=4.0Hz, 5H), 2.27-2.18 (m, 1H), 2.02-1.77 (m, 12H), 1.66 (dd, J=17.9, 8.9Hz, 2H), 1.47 (s, 3H), 1.36 (s, 3H).

Example 264(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using (3R)-3-fluoropyrrolidine hydrochloride to replacedimethylamine in THF (2.0 M) in Step 5. LCMS calc. for C₃₇H₄₈ClFN₃O₆S[M+H]⁺: m/z=716.3/718.3. Found: 716.4/718.2. ¹H NMR (300 MHz, CDCl₃) δ7.70 (d, J=8.5 Hz, 1H), 7.47 (dd, J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5,2.4 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.83 (d,J=2.2 Hz, 1H), 6.08-5.89 (m, 1H), 5.75 (dd, J=15.6, 6.7 Hz, 1H), 5.36(d, J=53.3 Hz, 1H), 4.66-4.24 (m, 2H), 4.20-3.96 (m, 4H), 3.84-3.69 (m,3H), 3.46 (qd, J=24.9, 22.1, 13.2 Hz, 7H), 3.14 (dd, J=15.0, 10.7 Hz,2H), 2.85-2.65 (m, 3H), 2.36-2.09 (m, 5H), 1.89-1.66 (m, 5H), 1.49 (s,3H), 1.32 (s, 3H).

Example 265(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-[(3S)-3-fluoropyrrolidin-1-yl]ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using (3S)-3-fluoropyrrolidine hydrochloride to replacedimethylamine in THF (2.0 M) in Step 5. LCMS calc. for C₃₇H₄₈ClFN₃O₆S[M+H]⁺: m/z=716.3/718.3. Found: 716.4/718.2. ¹H NMR (300 MHz, CDCl₃) δ7.68 (d, J=8.5 Hz, 1H), 7.48 (dd, J=8.3, 2.1 Hz, 1H), 7.18 (dd, J=8.5,2.4 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.89 (d,J=2.2 Hz, 1H), 6.08-5.84 (m, 1H), 5.72 (dd, J=15.7, 6.3 Hz, 1H), 5.33(d, J=53.0 Hz, 1H), 4.26 (t, J=9.1 Hz, 2H), 4.17-4.02 (m, 4H), 3.77 (t,J=14.1 Hz, 3H), 3.59-3.33 (m, 7H), 3.16 (dd, J=15.1, 10.3 Hz, 2H),2.82-2.74 (m, 3H), 2.28 (ddd, J=35.2, 19.4, 11.1 Hz, 5H), 1.95-1.64 (m,5H), 1.49 (s, 3H), 1.35 (s, 3H).

Example 266[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl](3R)-3-methoxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 1 and (3R)-3-methoxypyrrolidine hydrochloride inStep 2. LC-MS: calc. for C₃₆H₄₃ClN₃O₉S [M+H]⁻: m/z=728.2/730.2; Found:728.5/730.5. ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J=8.5 Hz, 1H), 7.48(ddd, J=7.8, 5.4, 2.1 Hz, 1H), 7.05 (dd, J=4.8, 2.2 Hz, 1H), 6.97 (d,J=8.3 Hz, 1H), 6.92 (dd, J=8.4, 2.2 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H),6.15-5.77 (m, 1H), 5.77-5.51 (m, 1H), 5.23 (d, J=8.3 Hz, 1H), 4.24 (dtd,J=31.1, 11.4, 8.1 Hz, 3H), 4.11-3.91 (m, 4H), 3.74-3.62 (m, 4H), 3.44(q, J=7.4, 6.2 Hz, 3H), 3.36 (s, 3H), 3.32 (s, 2H), 3.20-3.09 (m, 1H),2.79 (q, J=7.2 Hz, 2H), 2.06-1.95 (m, 3H), 1.85-1.77 (m, 2H), 1.60 (p,J=9.2 Hz, 1H), 1.42 (s, 3H), 1.33 (s, 3H).

Example 267(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-[methoxy(methyl)amino]ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using N,O-dimethylhydroxylamine hydrochloride to replacedimethylamine in THF (2.0 M) in Step 5. LCMS calc. for C₃₅H₄₇ClFN₃O₆S[M+H]⁺: m/z=688.3/690.3; Found: 688.3/690.3. ¹H NMR (300 MHz, CDCl₃) δ7.66 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5,2.4 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.03-6.92 (m, 2H), 5.87 (d, J=16.2Hz, 1H), 5.66 (dd, J=15.6, 6.5 Hz, 1H), 5.36 (d, J=1.0 Hz, 1H), 4.37 (s,3H), 4.18-3.99 (m, 4H), 3.84 (s, 3H), 3.74 (d, J=5.3 Hz, 1H), 3.68 (s,1H), 3.62-3.54 (m, 1H), 3.47-3.32 (m, 4H), 3.20 (dd, J=15.0, 9.5 Hz,1H), 3.09 (s, 3H), 2.79 (d, J=4.5 Hz, 3H), 2.32-2.21 (m, 1H), 2.01-1.90(m, 3H), 1.79 (q, J=9.4, 8.9 Hz, 2H), 1.47 (s, 3H), 1.37 (s, 3H).

Example 268(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(diethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using diethylamine in THF (2.0 M) to replacedimethylamine in THF (2.0 M) in Step 5. LCMS calc. for C₃₇H₅₁ClFN₃O₆S[M+H]⁺: m/z=700.3/702.3. Found: 700.3/702.3.

Example 269(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using (3S,4R)-3,4-difluoropyrrolidine hydrochloride toreplace dimethylamine in THF (2.0 M) in Step 5. LCMS calc. forC₃₇H₄₇ClF₂N₃O₆S [M+H]⁺: m/z=734.3/736.3. Found: 734.3/736.3.

Example 270(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-7-(2-morpholinoethoxy)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 using morpholine to replace dimethylamine in THF (2.0 M)in Step 5. LCMS calc. for C₃₇H₄₉ClN₃O₇S [M+H]⁺: m/z=714.29/716.29;Found: 714.7/716.8.

Example 271(3R,6R,7R,8E,22S)-6′-Chloro-12,12-dimethyl-7-(2-morpholinoethoxy)-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 36) in Step 1 and morpholine in Step 5. LCMS calc. forC₃₇H₄₉ClN₃O₇S [M+H]⁺: m/z=714.29/716.29; Found: 714.7/716.8. ¹H NMR (300MHz, CDCl₃) δ 9.43 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.54 (dd, J=8.3, 2.1Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.05-6.93(m, 2H), 5.92 (dt, J=15.7, 4.5 Hz, 1H), 5.73 (dd, J=15.7, 8.5 Hz, 1H),4.10 (d, J=2.0 Hz, 2H), 3.99 (m, 2H), 3.87 (d, J=6.5 Hz, 1H), 3.71 (dt,J=24.9, 14.9 Hz, 6H), 3.36-3.22 (m, 4H), 3.01 (m, 3H), 2.79 (m, 2H),2.45 (m, 1H), 2.40-2.32 (m, 1H), 2.24 (m, 1H), 1.99 (m, 3H), 1.84 (m,3H), 1.71-1.62 (m, 1H), 1.47 (m, 1H), 1.41 (d, J=15.2 Hz, 6H), 1.35-1.25(m, 2H).

Example 272(3R,6R,7R,8E,22S)-6′-Chloro-7-[2-(3,3-difluoroazetidin-1-yl)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 36) in Step 1 and 3,3-difluoroazetidine hydrochloride in Step5. LCMS calc. for C₃₆H₄₅ClF₂N₃O₆S [M+H]⁺: m/z=720.27/722.27; Found:720.7/722.7. ¹H NMR (300 MHz, CDCl₃) δ 9.47 (s, 1H), 7.70 (d, J=8.5 Hz,1H), 7.54 (dd, J=8.3, 2.1 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.10(d, J=2.3 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 5.91(dt, J=15.7, 4.6 Hz, 1H), 5.71 (dd, J=15.7, 8.6 Hz, 1H), 4.11 (s, 2H),3.99 (m, 2H), 3.91 (m, 1H), 3.87 (d, J=6.5 Hz, 1H), 3.77 (d, J=14.4 Hz,1H), 3.70 (dd, J=8.6, 4.9 Hz, 1H), 3.60 (m, 2H), 3.52 (m, 3H), 3.27 (m,2H), 3.07 (dd, J=15.1, 10.1 Hz, 1H), 2.78 (m, 2H), 2.46 (t, J=9.1 Hz,1H), 2.31 (dt, J=15.5, 9.8 Hz, 1H), 2.11-1.92 (m, 3H), 1.91-1.79 (m,2H), 1.68 (m, 2H), 1.50 (m, 1H), 1.41 (d, J=11.1 Hz, 6H), 1.30 (m, 2H).

Example 273(3R,6R,7R,8E,22S)-6′-Chloro-7-[2-(dimethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 36) in Step 1 and dimethylamine in THF (2 M) in Step 5. LCMScalc. for C₃₅H₄₇ClN₃O₆S [M+H]⁺: m/z=672.3/674.3; Found: 672.4/674.3. ¹HNMR (600 MHz, DMSO-d₆) δ 9.24 (s, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.26 (dd,J=8.5, 2.3 Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.82(d, J=2.3 Hz, 1H), 6.08 (d, J=13.9 Hz, 1H), 5.43 (dd, J=16.0, 8.7 Hz,1H), 4.14-4.03 (m, 3H), 3.74-3.66 (m, 2H), 3.61 (d, J=14.6 Hz, 1H), 3.54(m, 1H), 3.47 (m, 2H), 3.24 (m, 3H), 3.11 (dd, J=15.3, 10.2 Hz, 1H),2.79 (m, 7H), 2.73 (m, 1H), 2.39 (d, J=1.9 Hz, 1H), 2.10 (m, 1H), 1.98(m, 4H), 1.85 (m, 2H), 1.73-1.69 (m, 1H), 1.47 (m, 1H), 1.35 (s, 3H),1.23 (s, 3H).

Example 274(3R,6R,7R,8E,22S)-6′-Chloro-12,12-dimethyl-15,15-dioxo-7-(2-pyrrolidin-1-ylethoxy)spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 36) in Step 1 and pyrrolidine in Step 5. LCMS calc. forC₃₇H₄₈ClN₃O₆S [M+H]⁺: m/z=698.3/700.3; Found: 698.4/700.3. ¹H NMR (600MHz, DMSO-d₆) δ 9.37 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5,2.3 Hz, 2H), 7.23-7.16 (m, 1H), 7.05-6.99 (m, 1H), 6.83 (d, J=2.2 Hz,1H), 6.07 (d, J=16.2 Hz, 1H), 5.44 (dd, J=15.9, 8.8 Hz, 1H), 4.09 (m,3H), 3.67 (m, 1H), 3.61 (d, J=14.6 Hz, 1H), 3.55-3.41 (m, 6H), 3.19-2.95(m, 5H), 2.89-2.64 (m, 3H), 2.13-2.06 (m, 1H), 1.99 (m, 6H), 1.84 (m,4H), 1.71 (m, 2H), 1.47 (d, J=7.9 Hz, 1H), 1.36 (s, 3H), 1.23 (s, 3H).

Example 275(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(3-fluoroazetidin-1-yl)ethoxy]-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43) in Step 1 and 3-fluoroazetidine hydrochloride in Step 5.LCMS calc. for C₃₇H₄₉ClFN₄O₅S [M+H]⁺: m/z=715.31/717.31; Found:715.4/717.4.

Example 276(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethoxy]-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43) in Step 1 and (3R)-3-fluoropyrrolidine hydrochloride inStep 5. LCMS calc. for C₃₈H₅₁ClFN₄O₅S [M+H]⁺: m/z=729.32/731.31; Found:729.5/731.5.

Example 277(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]ethoxy]-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43) in Step 1 and 1-(2-methoxyethyl)-1,4-diazepane in Step 5.LCMS calc. for C₄₂H₆₁ClN₅O₆S [M+H]⁺: m/z=798.40/800.40; Found:798.5/800.5.

Example 278(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

To a solution of isobutoxycarbonyl2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxyacetate(40.0 mg, 0.05 mmol, Example 65 Step 3) in THF (4 mL) was addedtriethylamine (0.07 mL, 0.50 mmol). The mixture was stirred at r.t. for5 min, followed by adding of 3,3-difluoroazetidine hydrochloride (65.2mg, 0.50 mmol). The mixture was then stirred at r.t. for an additional 4h. LCMS showed that the starting material was consumed. The reaction wasquenched by 1N HCl (2 mL), and extracted with DCM (3 mL×2). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC on a C18 columnusing H₂O/ACN (20-100%) to afford(3R,6R,7S,8E,22S)-6′-chloro-7-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(9 mg, 21% yield). LCMS calc. for C₃₆H₄₃ClF₂N₃O₇S [M+H]⁺: m/z=734.2;Found: 734.5. ¹H NMR (300 MHz, CDCl₃) δ 9.08 (s, 1H), 7.72-7.58 (m, 1H),7.52 (m, 1H), 7.37 (dd, J=4.3, 2.0 Hz, 1H), 7.20 (dd, J=8.5, 2.4 Hz,1H), 7.12 (d, J=2.9 Hz, 1H), 7.02 (dd, J=8.5, 3.4 Hz, 1H), 5.85-5.48 (m,2H), 4.66 (m, 2H), 4.39 (m, 2H), 4.27-4.07 (m, 3H), 4.03-3.90 (m, 2H),3.88-3.64 (m, 3H), 3.52 (m, 1H), 3.42-3.28 (m, 2H), 2.89-2.63 (m, 3H),2.41 (m, 1H), 2.11-1.76 (m, 6H), 1.72-1.53 (m, 2H), 1.49-1.33 (m, 6H).

Example 279(3R,6R,7S,8E,22S)-7-[2-(Azetidin-1-yl)-2-oxo-ethoxy]-6′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 278 using azetidine hydrochloride to replace3,3-difluoroazetidine hydrochloride. LCMS calc. for C₃₆H₄₅ClN₃O₇S[M+H]⁺: m/z=698.2; Found: 698.3. ¹H NMR (300 MHz, CDCl₃) δ 9.17 (s, 1H),7.67 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.3, 2.1 Hz, 1H), 7.20 (dd, J=8.5,2.3 Hz, 1H), 7.13 (m, 2H), 7.00 (m, 1H), 6.83 (d, J=8.2 Hz, 1H), 5.77(m, 1H), 5.61 (dd, J=15.7, 6.4 Hz, 1H), 4.48-4.26 (m, 2H), 4.23-4.03 (m,5H), 4.01-3.65 (m, 5H), 3.46-3.33 (m, 2H), 3.26 (m, 2H), 2.80 (m, 2H),2.33 (m, 2H), 2.06-1.91 (m, 3H), 1.86 (m, 2H), 1.64 (s, 3H), 1.43 (d,J=20.2 Hz, 6H).

Example 280(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(3-methoxyazetidin-1-yl)-2-oxo-ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 278 using 3-methoxyazetidine hydrochloride to replace3,3-difluoroazetidine hydrochloride. LCMS calc. for C₃₇H₄₇ClN₃O₇S[M+H]⁺: m/z=728.2; Found: 728.3. 1H NMR (300 MHz, CDCl₃) δ 9.17 (s, 1H),7.67 (dd, J=8.5, 3.9 Hz, 1H), 7.52 (dd, J=8.4, 1.9 Hz, 1H), 7.20-7.10(m, 2H), 7.08-6.94 (m, 2H), 6.83 (d, J=8.3 Hz, 1H), 5.85-5.46 (m, 2H),4.65-4.39 (m, 1H), 4.39-4.17 (m, 3H), 4.15-3.84 (m, 6H), 3.82-3.67 (m,2H), 3.55 (q, J=6.9 Hz, 1H), 3.45-3.33 (m, 2H), 3.31 (d, J=10.4 Hz, 3H),3.23 (d, J=15.0 Hz, 1H), 2.83-2.69 (m, 2H), 2.45-2.29 (m, 1H), 2.29-2.14(m, 1H), 2.07-1.78 (m, 7H), 1.59-1.50 (m, 1H), 1.52-1.33 (m, 6H).

Example 281(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(3-fluoroazetidin-1-yl)-2-oxo-ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 278 using 3-fluoroazetidine hydrochloride to replace3,3-difluoroazetidine hydrochloride. LCMS calc. for C₃₆H₄₄ClFN₃O₇S[M+H]⁺: m/z=716.2; Found: 716.3. ¹H NMR (300 MHz, CDCl₃) δ 9.16 (d,J=22.6 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.52 (dd, J=8.3, 2.0 Hz, 1H),7.23-7.11 (m, 2H), 7.11-6.93 (m, 2H), 6.83 (d, J=7.8 Hz, 1H), 5.94-5.52(m, 2H), 5.33 (d, J=57.0 Hz, 1H), 4.89-4.57 (m, 1H), 4.46 (m, 2H),4.25-4.01 (m, 5H), 3.94-3.54 (m, 4H), 3.49-3.09 (m, 3H), 2.79 (m, 2H),2.36 (m, 1H), 2.12-1.76 (m, 5H), 1.65 (m, 3H), 1.56-1.34 (m, 6H).

Example 2822-[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15λ6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxy-N-tetrahydropyran-4-yl-acetamide

This compound was prepared using procedures analogous to those describedfor Example 278 using 4-aminotetrahydropyran to replace3,3-difluoroazetidine hydrochloride. LCMS calc. for C₈₃H₄₉ClN₃O₈S[M+H]⁺: m/z=742.29/744.28; Found: 742.4/744.3; ¹H NMR (300 MHz, CDCl₃) δ7.65 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.15 (d, J=8.7 Hz, 1H), 7.10 (d,J=2.2 Hz, 1H), 7.03 (d, J=2.1 Hz, 1H), 6.89 (s, 1H), 6.46 (s, 1H), 5.60(dd, J=15.4, 6.6 Hz, 1H), 4.10-3.78 (m, 10H), 3.68 (d, J=14.4 Hz, 1H),3.40-3.36 (m, 5H), 2.75 (d, J=18.9 Hz, 3H), 2.37 (d, J=9.6 Hz, 1H),1.91-1.84 (m, 9H), 1.66 (d, J=9.1 Hz, 1H), 1.50-1.48 (m, 2H), 1.39 (s,3H), 1.35 (s, 3H).

Example 283(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-15,15-dioxo-7-(2-oxo-2-pyrrolidin-1-yl-ethoxy)spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 278 using pyrrolidine to replace 3,3-difluoroazetidinehydrochloride. LCMS calc. for C₃₆H₄₃ClF₂N₃O₇S [M+H]⁺: m/z=712.2; Found:712.4. ¹H NMR (300 MHz, CDCl₃) δ 9.16 (s, 1H), 7.66 (d, J=8.5 Hz, 1H),7.52 (dd, J=8.3, 2.1 Hz, 1H), 7.23-7.16 (m, 1H), 7.11 (d, J=2.3 Hz, 1H),7.08-6.95 (m, 2H), 5.74 (dt, J=15.7, 4.6 Hz, 1H), 5.62 (dd, J=15.7, 6.7Hz, 1H), 4.19 (m, 2H), 4.13 (m, 2H), 4.01 (d, J=14.0 Hz, 1H), 3.92-3.84(m, 2H), 3.70 (d, J=14.6 Hz, 1H), 3.51 (m, 3H), 3.41 (m, 1H), 3.29 (dd,J=14.9, 8.4 Hz, 1H), 2.87-2.63 (m, 3H), 2.44 (dt, J=9.6, 4.8 Hz, 1H),1.92 (m, 8H), 1.60 (m, 2H), 1.42 (d, J=9.5 Hz, 6H).

Example 2842-[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15λ6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxy-N-[(3R)-tetrahydrofuran-3-yl]acetamide

This compound was prepared using procedures analogous to those describedfor Example 278 using (3R)-tetrahydrofuran-3-amine to replace3,3-difluoroazetidine hydrochloride. LCMS calc. for C₃₇H₄₇ClN₃O₈S[M+H]⁺: m/z=728.3/730.3; Found: 728.4/730.4. ¹H NMR (300 MHz, CDCl₃) δ9.38 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.53 (dd, J=8.3, 2.1 Hz, 1H), 7.20(dd, J=8.5, 2.3 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 7.05-6.98 (m, 2H), 6.89(d, J=7.7 Hz, 1H), 5.80 (ddd, J=16.0, 6.9, 3.3 Hz, 1H), 5.63 (dd,J=15.8, 5.9 Hz, 1H), 4.56 (ddt, J=10.5, 7.5, 3.2 Hz, 1H), 4.19-3.95 (m,6H), 3.87-3.74 (m, 6H), 3.42-3.20 (m, 3H), 2.80 (dt, J=12.3, 6.4 Hz,3H), 2.41-2.19 (m, 2H), 2.09-1.80 (m, 7H), 1.67 (t, J=9.3 Hz, 1H), 1.47(s, 3H), 1.39 (s, 3H).

Example 2852-[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15λ6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxy-N-[(3S)-tetrahydrofuran-3-yl]acetamide

This compound was prepared using procedures analogous to those describedfor Example 278 using (3S)-tetrahydrofuran-3-amine to replace3,3-difluoroazetidine hydrochloride. LCMS calc. for C₃₇H₄₇ClN₃O₈S[M+H]⁺: m/z=728.3/730.3; Found: 728.4/730.4. ¹H NMR (300 MHz, CDCl₃) δ9.44 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.20(dd, J=8.5, 2.2 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.04-6.98 (m, 2H), 5.81(ddd, J=15.9, 6.7, 3.6 Hz, 1H), 5.66 (dd, J=15.9, 6.1 Hz, 1H), 5.35-5.27(m, 1H), 4.58 (tt, J=7.3, 3.7 Hz, 1H), 4.19-3.94 (m, 6H), 3.88-3.65 (m,6H), 3.47-3.21 (m, 3H), 2.78 (dt, J=19.1, 5.7 Hz, 3H), 2.45-2.23 (m,2H), 2.10-1.80 (m, 7H), 1.67 (t, J=9.3 Hz, 1H), 1.46 (s, 3H), 1.39 (s,3H).

Example 286[(3R,6R,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-16,18,24-triene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

To a solution of(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate (35.0 mg, 0.05 mmol, Example 34) in ethyl acetate(3 mL) was added platinum(IV) oxide (2.36 mg, 0.01 mmol). The mixturewas then purged by H₂ gas in balloon for 2 times, and stirred at r.t.for 2 h under H₂ atmosphere. LCMS showed that most of the startingmaterial was consumed. The mixture was filtered through Celite andconcentrated under reduced pressure. The resulting residue was thenpurified by prep-HPLC on a C18 column using H₂O/ACN (20-100%) to provide[(3R,6R,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-16,18,24-triene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate (7.4 mg, 21.1% yield) as a white solid. LCMS calc.for C₃₄H₄₃ClN₃O₇S [M+H]⁺: m/z=674.26/677.26; Found: 674.7/679.6; ¹H NMR(600 MHz, DMSO-d₆) δ 7.61 (q, J=8.0 Hz, 1H), 7.31-7.16 (m, 4H), 7.00(dt, J=17.3, 8.5 Hz, 1H), 4.76-4.64 (m, 1H), 4.14-4.09 (m, 1H),4.06-4.00 (m, 1H), 3.54-3.43 (m, 3H), 3.25 (t, J=14.6 Hz, 2H), 3.10-2.96(m, 2H), 2.85-2.74 (m, 3H), 2.74-2.65 (m, 3H), 2.58 (d, J=14.1 Hz, 2H),2.24 (s, 1H), 1.96-1.89 (m, 2H), 1.85-1.73 (m, 3H), 1.73-1.52 (m, 5H),1.49-1.35 (m, 2H), 1.28 (s, 3H), 1.23 (d, J=16.5 Hz, 3H).

Example 287(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(3,3-difluoroazetidin-1-yl)ethoxy]-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43) in Step 1 and 3,3-difluoroazetidine hydrochloride in Step5. LCMS calc. for C₃₇H₄₈ClF₂N₄O₅S [M+H]⁺: m/z=733.30/735.30; Found:733.3/735.1. ¹H NMR (300 MHz, CDCl₃) δ 7.74-7.45 (m, 2H), 7.22-7.18 (m,2H), 7.09 (s, 1H), 7.03-6.89 (m, 1H), 6.02 (s, 1H), 5.71-5.46 (m, 1H),5.36 (s, 1H), 4.23-3.94 (m, 4H), 3.87 (d, J=18.4 Hz, 1H), 3.69 (s, 3H),3.33 (d, J=15.2 Hz, 2H), 3.06 (s, 1H), 2.79 (s, 3H), 2.46 (s, 2H), 2.25(t, J=7.7 Hz, 2H), 1.64 (d, J=7.4 Hz, 1H), 1.46 (s, 3H), 1.33 (s, 16H).

Example 288(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43) in Step 1 and 3,3-difluoropyrrolidine hydrochloride in Step5. LCMS calc. for C₃₈H₅₀ClF₂N₄O₅S [M+H]⁺: m/z=747.32/749.31; Found:747.4/749.3. ¹H NMR (300 MHz, CDCl₃) δ 7.71-7.49 (m, 1H), 7.39-7.12 (m,4H), 7.08-6.84 (m, 1H), 6.00 (s, 2H), 5.61 (d, J=17.9 Hz, 2H), 5.37 (s,2H), 3.72 (d, J=14.2 Hz, 4H), 3.52 (s, 3H), 3.11 (s, 1H), 2.80 (s, 1H),2.62 (m, 15H), 2.54 (s, 2H), 2.39-2.21 (m, 3H), 2.04 (s, 5H), 1.66 (d,J=7.4 Hz, 2H).

Example 289(3R,6R,7S,8E,22S)-6′-Chloro-11,12,12-trimethyl-15,15-dioxo-7-[2-(1-piperidyl)ethoxy]spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 65 Step 1-5 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(Example 43) in Step 1 and piperidine in Step 5. LCMS calc. forC₃₉H₅₄ClN₄O₅S [M+H]⁺: m/z=725.35/727.35; Found: 725.3/727.6. ¹H NMR (300MHz, CDCl₃) δ 11.57 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.3,2.0 Hz, 1H), 7.09 (d, J=2.3 Hz, 2H), 7.02-6.88 (m, 2H), 5.95 (d, J=45.7Hz, 2H), 5.60 (d, J=15.9 Hz, 1H), 5.42-5.28 (m, 1H), 4.20-4.00 (m, 3H),3.72 (dd, J=24.6, 13.3 Hz, 4H), 3.31 (d, J=14.6 Hz, 1H), 3.06 (s, 2H),2.53 (s, 3H), 2.38-2.20 (m, 2H), 2.00 (d, J=7.1 Hz, 1H), 1.84 (s, 3H),1.69-1.24 (m, 23H).

Example 290(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 278 using (3R,4R)-3,4-difluoropyrrolidine to replace3,3-difluoroazetidine hydrochloride. LCMS calc. for C₃₇H₄₅ClF₂N₃O₇S[M+H]⁺: m/z=748.3/750.3; Found: 748.4/750.4. ¹H NMR (300 MHz, CDCl₃) δ7.66 (d, J=8.5 Hz, 1H), 7.49 (dt, J=8.4, 1.7 Hz, 1H), 7.18 (dt, J=8.5,1.8 Hz, 1H), 7.09 (t, J=1.8 Hz, 1H), 7.05-6.95 (m, 2H), 5.82-5.53 (m,2H), 5.19 (ddd, J=50.3, 15.9, 4.2 Hz, 2H), 4.11-3.64 (m, 12H), 3.44-3.22(m, 3H), 2.84-2.69 (m, 3H), 2.37 (dd, J=9.2, 3.1 Hz, 1H), 2.03-1.78 (m,7H), 1.63 (d, J=17.3 Hz, 1H), 1.42 (s, 3H), 1.37 (s, 3H).

Example 291(3R,6R,7S,8E,22S)-6′-Chloro-7-[2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15%6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 278 using (3R,4S)-3,4-difluoropyrrolidine to replace3,3-difluoroazetidine hydrochloride. C₃₇H₄₅ClF₂N₃O₇S [M+H]⁺:m/z=748.3/750.3; Found: 748.4/750.4. ¹H NMR (300 MHz, CDCl₃) δ 7.65 (dd,J=8.5, 2.7 Hz, 1H), 7.48 (dt, J=8.4, 1.7 Hz, 1H), 7.18 (dt, J=8.5, 1.9Hz, 1H), 7.09 (d, J=2.1 Hz, 1H), 7.00 (ddd, J=8.4, 4.1, 1.7 Hz, 2H),5.85-5.56 (m, 2H), 5.26-4.95 (m, 2H), 4.17-3.66 (m, 12H), 3.45-3.17 (m,3H), 2.85-2.66 (m, 3H), 2.38 (dq, J=10.6, 5.4, 3.0 Hz, 1H), 2.07-1.78(m, 7H), 1.64 (t, J=8.7 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H).

Example 292[(3R,6R,7S,8E,22S)-6′-Chloro-10,12,12-trimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

Step 1: 2-methyl-2-(I-methylallyloxy)propanoic acid

To a solution of but-3-en-2-ol (410.0 mg, 5.69 mmol) and DIPEA (1.98 mL,11.37 mmol) in MeCN (5 mL) was added 2-bromo-2-methyl-propanoic acid(636.18 mg, 3.81 mmol). The reaction mixture was stirred at 50° C.overnight. Upon completion, the solvent was removed under reducedpressure. The residue was dissolved in DCM (10 mL) and washed with 1 NHCl solution (10 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure to yield2-methyl-2-(1-methylallyloxy)propanoic acid (450 mg, 50.0% yield), whichwas used for the next reaction without further purification. TLC:R_(f)=0.1 (Heptane:EtOAc=1:1).

Step 2:[1-[(1R,2R)-2-[[(3S)-6′-chloro-7-[[2-methyl-2-(1-methylallyloxy)propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]-1-methyl-allyl]2-methyl-2-(I-methylallyloxy)propanoate

To a solution of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]-methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(180.0 mg, 0.36 mmol, Intermediate 3) and2-methyl-2-(1-methylallyloxy)propanoic acid (169.81 mg, 1.07 mmol) inDCM (4 mL) was added 4-(dimethylamino)pyridine (262.28 mg, 2.15 mmol),followed by the addition of EDCI (274.37 mg, 1.43 mmol). The reactionmixture was stirred at r.t. overnight. The reaction was diluted with DCM(5 mL) and washed with 1N HCl solution (5 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure toyield[1-[(1R,2R)-2-[[(3S)-6′-chloro-7-[[2-methyl-2-(1-methylallyloxy)propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]-1-methyl-allyl]2-methyl-2-(1-methylallyloxy)propanoate (295 mg, 103.4% yield), whichwas used for the next reaction without further purification. LCMS calc.for C₄₃H₅₈ClN₂O₈S [M+H]⁺: m/z=783.34/785.34; Found: 783.6/785.5.

Step 3:N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-2-(I-methylallyloxy)propanamide

To a solution of[(1S)-1-[(1R,2R)-2-[[(3S)-6′-chloro-7-[[2-methyl-2-(1-methylallyloxy)propanoyl]sulfamoyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]allyl]2-methyl-2-(1-methylallyloxy)propanoate (295.0 mg, 0.38 mmol) in THF(0.50 mL), methanol (0.50 mL) and water (0.50 mL) was added lithiumhydroxide monohydrate (158.15 mg, 3.77 mmol). The reaction mixture wasstirred at 45° C. for 2 h. The solvent was removed under reducedpressure. The residue was dissolved in DCM (5 mL) and washed with sat.NaHCO₃solution (5 mL) and brine (5 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column eluting withEtOAc/Heptanes (5-30%) to afford the desired product N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-2-(1-methylallyloxy)propanamide(124 mg, 51.2% yield). LCMS calc. for C₃₄H₄₄ClN₂O₆S [M+H]⁺:m/z=643.24/645.24; Found: 643.4/645.3.

Step 4:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-10,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

To a solution ofN-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]-methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-2-(1-methylallyloxy)propanamide(124.0 mg, 0.19 mmol) in DCE (90 mL) was bubbled with N₂ for 20 min.Then Zhan catalyst (28.26 mg, 0.04 mmol) was added and was bubbled withN₂ for another 5 min. The reaction mixture was stirred at 45° C. for 2h. The solvent was removed under reduced pressure. The residue waspurified by flash chromatography on a silica gel column eluting withEtOAc/Heptanes with 0.2% HOAc (5-65%) to afford two products: P1 (18 mg,the earlier eluted product) and P2 (74 mg, the latter eluted product).The first fraction P1 was assigned to cis-isomer(3R,6R,7S,8Z,22S)-6′-chloro-7-hydroxy-10,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(18 mg, 15.2% yield). The P2 was assigned to the trans-isomer(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-10,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(74 mg, 62.4% yield). LCMS calc. for C₃₂H₄₀ClN₂O₆S [M+H]⁺:m/z=615.22/617.22; Found: 615.3/617.2.

Step 5:[(3R,6R,7S,8E,22S)-6′-chloro-10,12,12-trimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

To a solution of(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-10,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(15.0 mg, 0.02 mmol) in MeCN (1 mL) was added CDI (11.86 mg, 0.07 mmol).The reaction mixture was stirred at 45° C. for 2 h., and then cooled tor.t. Dimethylamine (0.025 mL, 0.05 mmol) (2.0 M in THF solution) wasadded. The reaction mixture was stirred at r.t. for 2 h. The reactionwas concentrated under reduced pressure. The residue was purified byPrep-HPLC on a C18 column eluting with ACN/H₂O (20%˜100%) to afford amixture of the two desired products: Fraction 1 (3.8 mg) contained about39% of Product 2 (Product 1/Product 2=55:35, Rt (P1)=8.02 min, Rt(P2)=8.18 min), and Fraction 2 (3.6 mg) contained 30% of Product 1(Product 1/Product 2=29:67, Rt (P1)=8.02 min, Rt (P2)=8.18 min).[(3R,6R,7S,8E,22S)-6′-chloro-10,12,12-trimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate (3.8 mg, 21.8% yield). LCMS calc. forC₃₅H₄₅ClN₃O₇S [M+H]⁺: m/z=686.26/688.26; Found: 686.4/688.4. ¹H NMR (600MHz, DMSO-d₆) δ 7.64 (dd, J=8.6, 4.5 Hz, 1H), 7.29-7.26 (m, 1H), 7.25(d, J=2.5 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.18 (dd, J=5.9, 2.4 Hz, 1H),7.04 (s, 1H), 5.66 (d, J=14.2 Hz, 1H), 5.17 (s, 1H), 4.19 (s, 1H), 4.00(d, J=12.2 Hz, 1H), 3.59 (d, J=14.3 Hz, 3H), 3.12 (s, 1H), 2.98 (s, 1H),2.85 (s, 2H), 2.75 (s, 6H), 2.62 (s, 1H), 2.03-1.95 (m, 2H), 1.89-1.79(m, 3H), 1.77-1.69 (m, 2H), 1.66-1.59 (m, 1H), 1.52-1.50 (m, 1H),1.47-1.40 (m, 1H), 1.32 (s, 6H), 1.24 (s, 3H).

Example 293[(3R,6R,7S,8E,22S)-6′-Chloro-7,12,12-trimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

Step 1:[(R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarbonyl]oxysodium

To a suspension of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-[[(1R,2R)-2-formylcyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(1450.0 mg, 2.03 mmol, Intermediate 3 Step 3) in 1-butanol (5 mL) and2-methylbut-2-ene (5.0 mL, 47.2 mmol) was added sodium chlorite (458.34mg, 4.05 mmol) and the solution of sodium phosphate monobasicmonohydrate (559.45 mg, 4.05 mmol) in water (5 mL). The reaction wasstirred at r.t. for 3 h. LCMS showed reaction was completed. Thereaction was quenched with aq. 10% Na2S₂O₃(5 mL) and the mixture wasextracted with ethyl acetate (2 mL×2). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was used directly without further purification. LCMS calc. forC₄₀H₄₂ClN₂O₇S [M−H]⁻: m/z=730.24/732.24; Found: 730.8/732.7.

Step 2:(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]-N-methoxy-N-methyl-cyclobutanecarboxamide

To a solution of[(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutanecarbonyl]oxysodium(300.0 mg, 0.40 mmol) and N,O-dimethylhydroxylamine hydrochloride (77.69mg, 0.80 mmol) in DCM (4 mL) was added DIPEA (0.28 mL, 1.59 mmol),followed by the addition of1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (302.86 mg, 0.80 mmol) at 0° C. The reactionmixture was stirred at r.t. for 2 h. The reaction was diluted with DCM(5 mL) and washed with 1 N HCl solution (5 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columneluting with EtOAc/Heptanes (5-50%) to afford the desired product(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]-N-methoxy-N-methyl-cyclobutanecarboxamide(232 mg, 75.2% yield). LCMS calc. for C₄₂H₄₉ClN₃O₇S [M+H]⁺:m/z=774.29/776.29; Found: 774.5/776.3.

Step 3:(3S)-5-[[(1R,2R)-2-acetylcyclobutyl]methyl]-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of methylmagnesium chloride THF solution (3 M in THF, 1.0mL, 3 mmol) was added a solution of(1R,2R)-2-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]-N-methoxy-N-methyl-cyclobutanecarboxamide(232.0 mg, 0.30 mmol) in THF (2 mL) dropwise at 0° C. After addition,the reaction mixture was stirred at r.t. for 2 h. The reaction wasquenched with aq. NH₄Cl solution (5 mL) at 0° C. and extracted withethyl acetate (5 mL×3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford thecrude(3S)-5-[[(1R,2R)-2-acetylcyclobutyl]methyl]-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(300 mg) which contaminated with some inorganic salt and was used forthe next reaction without further purification. LCMS calc. forC₄₁H₄₆ClN₂O₆S [M+H]⁺: m/z=729.27/731.27; Found: 729.5/731.4.

Step 4:(3S)-5-[[(1R,2R)-2-acetylcyclobutyl]methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of(3S)-5-[[(1R,2R)-2-acetylcyclobutyl]methyl]-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(300.0 mg, 0.41 mmol) in DCM (3 mL) was added Anisole (0.3 mL, 2.76mmol) and TFA (3.0 mL, 39.2 mmol). The reaction mixture was stirred atr.t. overnight. The solvent was removed under reduced pressure. Theresidue was dissolved in DCM (5 mL) and washed with sat. NaHCO₃solution(5 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column eluting with EtOAc/Heptanes(5-70%) to afford the desired product(3S)-5-[[(1R,2R)-2-acetylcyclobutyl]methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(220 mg). LCMS calc. for C₂₅H₃₀ClN₂₀₄S [M+H]⁺: m/z=489.15/491.15; Found:489.2/491.4.

Step 5:(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxy-1-methyl-allyl]cyclobutyl]methylspiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a solution of vinylmagnesium bromide THF solution (1.0 M in THF, 4.5mL, 4.5 mmol) was added a solution of(3S)-5-[[(1R,2R)-2-acetylcyclobutyl]methyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(220.0 mg, 0.45 mmol) in THF (1 mL) dropwise at 0° C. After addition,the reaction mixture was stirred at r.t. for 2 h. The reaction wasquenched by aq. NH₄Cl (5 mL) and extracted with ethyl acetate (5 mL×3).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column eluting with EtOAc/Heptanes(5-70%) to afford the desired product(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxy-1-methyl-allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(85 mg, 36.5% yield). LCMS calc. for C₂₇H₃₃ClN₂O₄S [M+H]⁺:m/z=517.18/519.18; Found: 517.2/519.3.

Step 6:[(1S)-1-[(R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propanoyl)sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]-1-methyl-allyl]2-allyloxy-2-methyl-propanoate

To a mixture of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxy-1-methyl-allyl]-cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(85.0 mg, 0.16 mmol) and 2-allyloxy-2-methyl-propanoic acid (71.1 mg,0.49 mmol, Example 30 Step 1) in DCM (1 mL) was added DMAP (120.5 mg,0.99 mmol), followed by the addition of EDCI (126.05 mg, 0.66 mmol). Thereaction mixture was stirred at r.t. overnight, and then diluted withDCM (5 mL). The mixture was and washed with 1N HCl solution (5 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield[(1S)-1-[(1R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propanoyl)sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]-1-methyl-allyl]2-allyloxy-2-methyl-propanoate (136 mg) which was directly used for thenext reaction without further purification. LCMS calc. for C₄₁H₅₄ClN₂₀₈S[M+H]⁺: m/z=769.32/771.32; Found: 769.5/771.5.

Step 7:2-allyloxy-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxy-1-methyl-allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-propanamide

To a solution of[(1S)-1-[(1R,2R)-2-[[(3S)-7-[(2-allyloxy-2-methyl-propanoyl)sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]cyclobutyl]-1-methyl-allyl]2-allyloxy-2-methyl-propanoate (136.0 mg, 0.18 mmol) in THF (0.50 mL),methanol (0.50 mL) and water (0.50 mL) was added lithium hydroxidemonohydrate (74.24 mg, 1.77 mmol). The reaction mixture was stirred at45° C. for 6 h. The solvent was removed under reduced pressure. Theresidue was dissolved in DCM (5 mL) and washed with 1N HCl solution (5mL). The organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon a silica gel column eluting with EtOAc/Heptanes (5-60%) to afford thedesired product2-allyloxy-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxy-1-methyl-allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-propanamide(83 mg, 73.0% yield). LCMS calc. for C₃₄H₄₄ClN₂O₆S [M+H]⁺:m/z=643.25/645.25; Found: 643.4/645.5.

Step 8:(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-7,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

To a solution of2-allyloxy-N-[(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxy-1-methyl-allyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonyl-2-methyl-propanamide(83.0 mg, 0.13 mmol) in DCE (80 mL) was bubbled with N₂ for 20 min. ThenZhan catalyst (18.92 mg, 0.03 mmol) was added and was bubbled with N₂for another 5 min. The reaction mixture was stirred at 45° C. for 2 h.Upon completion, the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columneluting with EtOAc/Heptanes (5-60%), and further purified with Prep-HPLCon a C18 column eluting with ACN/H₂O (20%˜100%) to afford the desiredproduct(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-7,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one(2.6 mg, 3.3% yield). LCMS calc. for C₃₂H₄₀ClN₂O₆S [M+H]⁺:m/z=615.23/617.23; Found: 615.4/617.5. ¹H NMR (300 MHz, CDCl₃) δ 7.68(d, J=8.5 Hz, 1H), 7.47 (s, 1H), 7.18 (d, J=9.2 Hz, 1H), 7.07 (d, J=2.3Hz, 1H), 6.95 (s, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.05 (s, 1H), 5.78 (d,J=15.4 Hz, 1H), 4.09 (s, 3H), 3.85-3.67 (m, 2H), 3.46 (d, J=14.5 Hz,1H), 3.39-3.29 (m, 1H), 3.02 (d, J=14.2 Hz, 1H), 2.74 (d, J=19.5 Hz,3H), 2.03-1.89 (m, 3H), 1.81 (t, J=8.5 Hz, 2H), 1.69 (s, 4H), 1.41 (s,3H), 1.36 (s, 3H), 1.24 (d, J=7.2 Hz, 3H).

Step 9:[(3R,6R,7S,8E,22S)-6′-chloro-7,12,12-trimethyl-13,15,15-trioxo-spiro[11,20-dioxa-1S-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-7,12,12-trimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-oneand dimethylcarbamoyl chloride. LCMS calc. for C₃₅H₄₅ClN₃O₇S [M+H]⁺:m/z=686.26/688.26; Found: 686.4/688.4. ¹H NMR (300 MHz, CDCl₃) δ 7.70(d, J=8.5 Hz, 1H), 7.48 (dd, J=8.3, 2.2 Hz, 1H), 7.19 (dd, J=8.5, 2.4Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.93 (d, J=2.1Hz, 1H), 6.04 (d, J=15.8 Hz, 1H), 5.85-5.71 (m, 1H), 4.09 (d, J=3.7 Hz,2H), 3.92-3.83 (m, 1H), 3.78 (d, J=14.6 Hz, 1H), 3.59 (d, J=15.1 Hz,1H), 3.34 (d, J=14.3 Hz, 1H), 3.10 (dd, J=15.1, 10.8 Hz, 1H), 2.94 (d,J=5.1 Hz, 6H), 2.79 (s, 2H), 2.24 (t, J=9.1 Hz, 1H), 2.01 (d, J=6.3 Hz,2H), 1.85 (d, J=8.9 Hz, 1H), 1.65 (d, J=8.8 Hz, 7H), 1.61 (s, 3H), 1.43(s, 3H), 1.36 (s, 3H).

Example 294[(3R,6R,7S,8E,15S,25S)-6′-Chloro-16,18,18-trioxo-spiro[23-oxa-18-thia-1,11,17-triazapentacyclo[17.7.2.03,6.011,15.022,27]octacosa-8,19,21,27-tetraene-25,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 292 Step 2-5 using (2S)-1-allylpyrrolidine-2-carboxylic acidHCl (Example 100 Step 2) and(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-hydroxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(Intermediate 3) in Step 2, and dimethylcarbamoyl chloride in Step 5.LCMS calc. for C₃₅H₄₄ClN₅O₆S [M+H]⁺: m/z=683.26/685.26; Found:683.4/685.4. ¹H NMR (300 MHz, DMSO-d₆) δ 8.96 (s, 1H), 7.62 (dd, J=8.6,1.8 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz, 1H), 7.16 (dd, J=3.7, 2.1 Hz, 2H),6.99 (dd, J=8.1, 1.8 Hz, 1H), 6.76 (dd, J=8.2, 1.7 Hz, 1H), 5.88 (dd,J=15.6, 3.0 Hz, 1H), 5.18 (d, J=10.9 Hz, 1H), 5.08-4.93 (m, 1H), 4.05(d, J=12.2 Hz, 1H), 3.92 (d, J=12.3 Hz, 1H), 3.75-3.58 (m, 3H),3.57-3.42 (m, 3H), 3.17 (s, 1H), 3.14-3.08 (m, 1H), 3.05 (d, J=4.4 Hz,1H), 2.96 (d, J=6.6 Hz, 1H), 2.78-2.70 (m, 1H), 2.66 (s, 3H), 2.51 (s,3H), 2.41 (t, J=8.0 Hz, 2H), 2.33-2.24 (m, 1H), 2.15-1.85 (m, 5H),1.79-1.59 (m, 5H), 1.38 (d, J=10.2 Hz, 1H).

Example 295[(3R,6R,7S,8E,22S)-6′-Chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[(3S)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-6′-chloro-7-hydroxy-11-methyl-12,12-(1,3-propylene)-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one(Example 48 Step 8) in Step 2 and (3S)-tetrahydrofuran-3-amine inStep 1. LCMS calc. for C₃₈H₄₈ClN₄O₇S [M+H]⁺: m/z=739.29/741.29; Found:739.3/741.4.

Example 296(23S)-6′-Chloro-16,16-dioxo-spiro[21-oxa-16-thia-1,6,12,15,27-pentazapentacyclo[15.7.2.13,6.19,12.020,25]octacosa-9(27),10,17,19,25-pentaene-23,1′-tetralin]-7,14-dione

Step 1: ethyl 2-[1-(2-tert-butoxy-2-oxo-ethyl)pyrazol-3-yl]acetate

To a mixture of ethyl 2-(1H-pyrazol-3-yl)acetate (1.0 g, 6.49 mmol) andcesium carbonate (4.25 g, 12.97 mmol) in DMF (35 mL) was added t-butylbromoacetate (1.9 g, 9.73 mmol) dropwise. The mixture was stirred atr.t. overnight. The mixture was diluted with ethyl acetate (50 mL),washed with water (30 mL×3). The organic layer was dried over Na₂SO₄,filtered, and concentrated. The residue was purified with reverse phaseHPLC (0.01% ammonia in water and acetonitrile) to get ethyl2-[1-(2-tert-butoxy-2-oxo-ethyl)pyrazol-3-yl]acetate (370.5 mg, 20.6%yield) as a pale yellow oil. LCMS calc. for C₁₃H₂₁N₂O₄ [M+H]⁺:m/z=269.14; Found: 269.1. ¹H NMR (400 MHz, CDCl₃-d) δ 1.26 (t, J=7.2 Hz,3H), 1.47 (s, 9H), 3.69 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 4.77 (s, 2H),6.30 (d, J=2.4 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H).

Step 2: 2-[1-(2-tert-butoxy-2-oxo-ethyl)pyrazol-3-yl]acetic acid

To a stirred solution of ethyl2-[1-(2-tert-butoxy-2-oxo-ethyl)pyrazol-3-yl]acetate (128.0 mg, 0.48mmol) in THF (1 mL), water (1 mL) and methanol (1 mL) was added lithiumhydroxide monohydrate (22.02 mg, 0.52 mmol). The resulting mixture wasstirred at r.t. overnight. LCMS indicated the consumption of startingmaterial and the formation of desired product. Water (5 mL) was addedfollowed by 5 mL of DCM. The pH of aqueous layer was adjusted to 2˜3 byadding 0.1 M HCl. The layers were separated, and the aqueous layer wasextracted with EtOAc (10 mL×3). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column (12g) with EtOAc/Heptanes (20% to 100%) to afford2-[1-(2-tert-butoxy-2-oxo-ethyl)pyrazol-3-yl]acetic acid (115 mg) as alight yellow solid. LCMS calc. for C₁₁H₁₅N₂O₄S [M−H]⁻: m/z=239.1; Found:239.2.

Step 3: tert-butyl3-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]pyrrolidine-1-carboxylate

To a stirred solution of(3S)-6′-chloro-N,N-bis[(4-methoxyphenyl)methyl]spiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(1.0 g, 1.62 mmol, Intermediate 2) in DCM (3 mL) was added tert-butyl3-formylpyrrolidine-1-carboxylate (0.39 g, 1.94 mmol). The resultingmixture was then cooled to 0° C. TFA (1.24 mL, 16.15 mmol) was added tothis solution followed by sodium borohydride (1.22 g, 32.3 mmol). Theresulting mixture was further stirred at 0° C. for 30 min., then slowlywarmed up to r.t. LCMS showed the consumption of starting material andthe formation of desired product. MeOH (2 mL) was added to quench thereaction. Water (10 mL) was added followed by 10 mL of DCM. The pH ofaqueous layer was adjusted to 7-8 by adding saturated sodium bicarbonatesolution. The layers were separated, and the aqueous layer was extractedwith DCM (10 mL×2). The combined organic layers were dried over Na₂SO₄,filtered and concentrated to afford tert-butyl3-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]pyrrolidine-1-carboxylate(660 mg, 50.9% yield) which was used in next step without furtherpurification. LCMS calc. for C₄₄H₅₃ClN₃O₇S [M+H]⁺: m/z=802.3/804.3;Found: 802.5/804.6.

Step 4:(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide

To a stirred solution of tert-butyl3-[[(3S)-7-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]pyrrolidine-1-carboxylate(0.66 g, 0.82 mmol) in DCM (10 mL) was added TFA slowly. The resultingmixture was kept stirring at r.t. overnight. The reaction was slowlypoured into 100 mL of saturated sodium carbonate solution under an icebath. Then the mixture was extracted with DCM (50 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated toafford(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(400 mg) as a white solid. The crude product was used in next stepwithout further purification. LCMS calc. for C₂₃H₂₉ClN₃O₃S [M+H]⁺:m/z=462.2/464.2; Found: 462.6/464.5.

Step 5: tert-butyl3-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]pyrrolidine-1-carboxylate

To a solution of(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-sulfonamide(160.0 mg, 0.35 mmol) in methanol (5 mL) was added di-tert butyldicarbonate (113.38 mg, 0.52 mmol). The resulting mixture was stirred atr.t. LCMS indicated the consumption of starting material and theformation of desired product. Water (20 mL) was added and extracted withDCM (20 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography on a silica gel column (12 g) with EtOAc/Heptanes (20% to100%) to afford tert-butyl3-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]pyrrolidine-1-carboxylate(103 mg, 52.9% yield) as a colorless oil. LCMS calc. for C₂₈H₃₇ClN₃O₅S[M+H]⁺: m/z=562.2/564.2; Found: 562.5/564.7.

Step 6: tert-butyl3-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl3-[[(3S)-6′-chloro-7-sulfamoyl-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]pyrrolidine-1-carboxylate(80.0 mg, 0.14 mmol) in DCM (2 mL) was added2-[1-(2-tert-butoxy-2-oxo-ethyl)pyrazol-3-yl]acetic acid (68.39 mg, 0.28mmol) followed by EDCI (0.06 mL, 0.28 mmol) and DMAP (69.55 mg, 0.57mmol). The resulting mixture was stirred at r.t. overnight. The reactionwas quenched by adding 5 mL of 1 M HCl (5 mL) and extracted with DCM (5mL×3). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC on a C18 column (30×250 mm, 10 m) with MeCN/H₂O (20% to 100%)to afford tert-butyl3-[[(3S)-7-[[2-[1-(2-tert-butoxy-2-oxo-ethyl)pyrazol-3-yl]acetyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]pyrrolidine-1-carboxylate(62 mg, 55.5% yield) as a white solid. LCMS calc. for C₃₉H₅₁ClN₅O₈S[M+H]⁺: m/z=784.3/786.3; Found: 784.5/786.5.

Step 7:2-[3-[2-oxo-2-[[(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]ethyl]pyrazol-1-yl]aceticacid

To a stirred solution of tert-butyl3-[[(3S)-7-[[2-[1-(2-tert-butoxy-2-oxo-ethyl)pyrazol-3-yl]acetyl]sulfamoyl]-6′-chloro-spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-5-yl]methyl]pyrrolidine-1-carboxylate(62.0 mg, 0.08 mmol) in DCM (2 mL) was added phosphoric acid (0.05 mL,0.79 mmol). The resulting mixture was stirred at r.t. for 24 h. Thesolution was slowly poured into a 30 mL of saturated sodium bicarbonatesolution and the pH of aqueous layer was adjusted to ˜4-5 by adding 1 MHCl. The mixture was extracted with EtOAc (10 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by prep-HPLC on a C18 column (30×250 mm, 10 m) withMeCN/H₂O (20% to 100%) to afford2-[3-[2-oxo-2-[[(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]ethyl]pyrazol-1-yl]aceticacid (31 mg, 50.0% yield) as a white solid. LCMS calc. for C₃₀H₃₅ClN₅O₆S[M+H]⁺: m/z=628.2/630.2; Found: 628.4/630.5.

Step 8:(23S)-6′-chloro-16,16-dioxo-spiro[21-oxa-16-thia-1,6,12,15,27-pentazapentacyclo[15.7.2.13,6.19,12.020,25]octacosa-9(27),10,17,19,25-pentaene-23,1′-tetralin]-7,14-dione

To a stirred solution of2-[3-[2-oxo-2-[[(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]ethyl]pyrazol-1-yl]aceticacid (31.0 mg, 0.05 mmol) in DMF (25 mL) was added HATU (56.3 mg, 0.15mmol) followed by DIPEA (0.03 mL, 0.15 mmol). The resulting solution wasstirred at r.t. for 2 h. Water (50 mL) was added, and extracted withethyl acetate (25 mL×3). The combined organic layers were washed withwater (25 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC on a C18 column(30×250 mm, 10 m) with MeCN/H₂O (20% to 100%) to afford(23S)-6′-chloro-16,16-dioxo-spiro[21-oxa-16-thia-1,6,12,15,27-pentazapentacyclo[15.7.2.13,6.19,12.020,25]octacosa-9(27),10,17,19,25-pentaene-23,1′-tetralin]-7,14-dione(9.1 mg, 30.2% yield) as a white solid. LCMS calc. for C₃₀H₃₃ClN₅O₅S[M+H]⁺: m/z=610.2/612.2; Found: 610.4/612.3.

Example 297(23S)-6′-Chloro-16,16-dioxo-spiro[21-oxa-thia-1,6,9,15,27-pentazapentacyclo[15.7.2.13,6.19,12.020,25]octacosa-10,12(27),17,19,25-pentaene-23,1′-tetralin]-7,14-dione

Step 1: 2-[1-(2-ethoxy-2-oxo-ethyl)pyrazol-3-yl]acetic acid

This compound was prepared using procedures analogous to those describedfor Example 296 Step 1-2 using tert-butyl 2-(1H-pyrazol-3-yl)acetate andethyl bromoacetate in Step 1. LCMS calc. for C₉H14N204 [M+H]⁺:m/z=213.1; Found: 213.2.

Step 2: ethyl2-[3-[2-[[(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-2-oxo-ethyl]pyrazol-1-yl]acetate

This compound was prepared using procedures analogous to those describedfor Example 296 Step 6-7 using2-[1-(2-ethoxy-2-oxo-ethyl)pyrazol-3-yl]acetic acid to replace2-[1-(2-tert-butoxy-2-oxo-ethyl)pyrazol-3-yl]acetic acid in Step 6. LCMScalc. for C₃₂H₃₉ClN₅O₆S [M+H]⁺: m/z=656.2/658.2; Found: 656.4/658.4.

Step 3:2-[3-[2-[[(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-2-oxo-ethyl]pyrazol-1-yl]aceticacid

To a solution of ethyl2-[3-[2-[[(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-2-oxo-ethyl]pyrazol-1-yl]acetate(25.0 mg, 0.04 mmol) in methanol (0.50 mL) and THF (0.50 mL) was addedlithium hydroxide monohydrate (4.8 mg, 0.11 mmol) in water (0.50 mL).The resulting solution was stirred at 40° C. for 2 h. The reactionmixture was quenched with 1M HCl aqueous solution to pH 5-6 andextracted with EtOAc. The combined organic layers were concentratedunder reduced pressure to afford2-[3-[2-[[(3S)-6′-chloro-5-(pyrrolidin-3-ylmethyl)spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-yl]sulfonylamino]-2-oxo-ethyl]pyrazol-1-yl]aceticacid (21 mg, 87.7% yield) as a white solid. LC-MS: calc. forC₃₀H₃₅ClN₅O₆S [M+H]⁺: m/z=628.1/630.2; Found: 628.3/630.2.

Step 4:(23S)-6′-chloro-16,16-dioxo-spiro[21-oxa-thia-1,6,9,15,27-pentazapentacyclo[15.7.2.13,6.19,12.020,25]octacosa-10,12(27),17,19,25-pentaene-23,1′-tetralin]-7,14-dione

This compound was prepared using procedures analogous to those describedfor Example 296 Step. LCMS calc. for C₃₀H₃₃ClN₅O₅S [M+H]⁺:m/z=610.2/612.2; Found 610.2/612.2.

Example 298[(3R,6R,7S,8E,22R)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-isochromane]-7-yl]N-methyl-N-(oxetan-3-yl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22R)-6′-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-isochromane]-13-one(Example 249) in Step 2 and N-methyloxetan-3-amine in Step 1. LCMS calc.for C₃₅H₄₃ClN₃O₉S [M+H]⁺: m/z=716.23/718.23; Found: 716.0/718.1. ¹H NMR(300 MHz, Chloroform-d) δ 7.54 (dd, J=8.3, 2.1 Hz, 1H), 7.49 (d, J=8.5Hz, 1H), 7.25 (d, J=2.3 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.10 (d, J=2.3Hz, 1H), 7.01 (dd, J=8.4, 1.1 Hz, 1H), 5.93-5.83 (m, 1H), 5.67 (dd,J=15.6, 5.9 Hz, 1H), 4.92-4.74 (m, 5H), 4.33 (d, J=11.8 Hz, 1H), 4.16(d, J=11.8 Hz, 1H), 4.05-3.93 (m, 3H), 3.66 (td, J=15.5, 14.8, 4.6 Hz,4H), 3.34 (dd, J=15.0, 5.2 Hz, 1H), 3.16 (s, 3H), 2.96 (dd, J=9.1, 6.0Hz, 1H), 2.83-2.70 (m, 2H), 2.47-2.35 (m, 1H), 2.16-2.05 (m, 1H), 1.88(q, J=10.6, 9.9 Hz, 2H), 1.65 (d, J=9.5 Hz, 2H), 1.43 (s, 3H), 1.35 (s,3H).

Example 299[(3R,6R,7S,8E,22R)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-isochromane]-7-yl]N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22R)-6′-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-isochromane]-13-one(Example 249) in Step 2 and and (3R)—N-methyltetrahydrofuran-3-aminehydrochloride in Step 1. LCMS calc. for C₃₆H₄₅ClN₃O₉S [M+H]⁺:m/z=730.25/732.25; Found: 730.0/732.2. ¹H NMR (300 MHz, Chloroform-d) δ7.53 (dd, J=8.3, 2.1 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.26 (dd, J=8.4,2.2 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.01 (d,J=8.4 Hz, 1H), 5.93-5.82 (m, 1H), 5.67 (dd, J=15.7, 5.6 Hz, 1H), 5.34(s, 1H), 4.96 (s, 1H), 4.33 (d, J=11.8 Hz, 1H), 4.16 (d, J=11.8 Hz, 1H),4.10-3.91 (m, 4H), 3.80 (s, 2H), 3.74-3.50 (m, 5H), 3.37 (d, J=5.1 Hz,1H), 2.95 (s, 3H), 2.90-2.82 (m, 1H), 2.81-2.69 (m, 1H), 2.48-2.36 (m,1H), 2.26 (ddd, J=13.1, 8.9, 4.8 Hz, 1H), 2.17-2.00 (m, 2H), 1.89 (dq,J=19.4, 9.4 Hz, 3H), 1.66 (t, J=9.4 Hz, 2H), 1.44 (s, 3H), 1.35 (s, 3H).

Example 300[(3R,6R,7S,8E,22R)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-isochromane]-7-yl]N-methyl-N-tetrahydropyran-4-yl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22R)-6′-Chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-isochromane]-13-one(Example 249) in Step 2 and N-methyltetrahydropyran-4-amine in Step 1.LCMS calc. for C₃₇H₄₇ClN₃O₉S [M+H]⁺: m/z=744.26/746.26; Found:744.1/746.2. ¹H NMR (300 MHz, Chloroform-d) δ 7.59-7.44 (m, 2H), 7.26(dd, J=8.4, 2.2 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H),7.01 (d, J=8.4 Hz, 1H), 5.86 (d, J=16.0 Hz, 1H), 5.66 (d, J=16.1 Hz,1H), 5.34 (s, 1H), 4.33 (d, J=11.8 Hz, 1H), 4.17 (d, J=11.9 Hz, 1H),4.10-3.88 (m, 5H), 3.75-3.59 (m, 4H), 3.46 (d, J=11.9 Hz, 1H), 3.35 (dd,J=15.0, 5.4 Hz, 1H), 3.05-2.95 (m, 1H), 2.88 (d, J=17.0 Hz, 3H), 2.76(dt, J=16.3, 3.8 Hz, 1H), 2.50-2.34 (m, 1H), 2.15-1.99 (m, 1H), 1.88(dd, J=21.4, 10.2 Hz, 4H), 1.66 (t, J=9.0 Hz, 6H), 1.43 (s, 3H), 1.35(s, 3H).

Example 301[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 2 and (3R)—N-methyltetrahydrofuran-3-aminehydrochloride in Step 1. LCMS calc. for C₃₆H₄₅ClN₃O₉S [M+H]⁺:m/z=730.25/732.25; Found: 730.1/732.1. ¹H NMR (300 MHz, CDCl₃) δ 9.10(s, 1H), 7.60-7.48 (m, 2H), 7.06-6.99 (m, 2H), 6.93 (dt, J=8.5, 1.6 Hz,1H), 6.86 (d, J=2.1 Hz, 1H), 5.87-5.63 (m, 2H), 5.27 (d, J=16.4 Hz, 2H),4.91 (s, 1H), 4.36-4.00 (m, 7H), 3.84-3.68 (m, 5H), 3.49-3.32 (m, 2H),3.23 (dd, J=15.0, 8.9 Hz, 1H), 2.91 (s, 3H), 2.41 (qd, J=9.3, 3.3 Hz,1H), 2.27 (dtd, J=13.3, 8.4, 4.8 Hz, 1H), 2.09-1.98 (m, 2H), 1.91-1.77(m, 3H), 1.66 (q, J=9.4 Hz, 1H), 1.44 (s, 3H), 1.36 (s, 3H).

Example 302[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]N-[(3R)-tetrahydrofuran-3-yl]carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 1 and (3R)-tetrahydrofuran-3-amine in Step 2. LCMScalc. for C₃₅H₄₃ClN₃O₉S [M+H]⁺: m/z=716.23/718.23; Found: 716.52/718.09.¹H NMR (300 MHz, CDCl₃) δ 9.05 (s, 1H), 7.54 (t, J=14.5 Hz, 2H), 7.14(s, 1H), 7.05 (d, J=8.3 Hz, 1H), 6.95 (dd, J=8.4, 2.0 Hz, 1H), 6.88 (d,J=1.9 Hz, 1H), 5.83-5.64 (m, 2H), 5.18 (s, 1H), 4.26 (m, 3H), 4.16-4.07(m, 2H), 4.03-3.95 (m, 1H), 3.86 (d, J=5.8 Hz, 2H), 3.77 (d, J=13.5 Hz,2H), 3.44 (t, J=12.4 Hz, 2H), 3.22 (d, J=6.9 Hz, 3H), 2.79 (d, J=6.4 Hz,1H), 2.40 (s, 1H), 2.32-2.20 (m, 1H), 2.11-1.99 (m, 2H), 1.83 (dd,J=32.2, 8.6 Hz, 4H), 1.69-1.60 (m, 1H), 1.44 (s, 3H), 1.39 (s, 3H).

Example 303[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]N-methyl-N-(oxetan-3-yl)carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 2 and N-methyloxetan-3-amine in Step 1. LCMS calc.for C₃₅H₄₁ClN₃O₉S [M−H]⁻: m/z=714.2/716.2; Found 713.8/715.8. ¹H NMR(300 MHz, CDCl₃) δ 7.56 (dd, J=8.4, 2.1 Hz, 2H), 7.05 (dd, J=8.3, 1.8Hz, 2H), 6.95 (dd, J=8.6, 2.2 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 5.74 (t,J=8.0 Hz, 2H), 5.28 (d, J=4.6 Hz, 1H), 4.89-4.73 (m, 3H), 4.43-3.98 (m,6H), 3.87-3.69 (m, 3H), 3.50-3.20 (m, 3H), 3.12 (s, 3H), 2.50-2.32 (m,1H), 2.25 (t, J=7.6 Hz, 1H), 2.17-1.76 (m, 7H), 1.46 (s, 3H), 1.37 (s,3H).

Example 304[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]N-methyl-N-tetrahydropyran-4-yl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 2 and N-methyltetrahydropyran-4-amine in Step 1.LCMS calc. for C₃₇H₄₇ClN₃O₉S [M+H]⁺: m/z=744.26/746.26; Found:744.2/746.2. ¹H NMR (300 MHz, CDCl₃) δ 9.04 (s, 1H), 7.60-7.46 (m, 2H),7.09-6.99 (m, 2H), 6.93 (dd, J=8.4, 2.2 Hz, 1H), 6.86 (d, J=2.1 Hz, 1H),5.84-5.63 (m, 2H), 5.31 (t, J=4.3 Hz, 1H), 4.39-3.92 (m, 9H), 3.76 (t,J=12.2 Hz, 2H), 3.52-3.34 (m, 4H), 3.27 (d, J=8.8 Hz, 1H), 2.85 (s, 3H),2.51-2.35 (m, 1H), 2.12-1.98 (m, 2H), 1.81 (q, J=12.0, 10.8 Hz, 4H),1.65 (d, J=6.8 Hz, 4H), 1.44 (s, 3H), 1.36 (s, 3H).

Example 305[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]N-tetrahydropyran-4-yl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 1 and tetrahydropyran-4-amine in Step 2. LCMScalc. for C₃₆H₄₅ClN₃O₉S [M+H]⁺: m/z=730.25/732.25; Found: 730.2/732.2.¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 7.61-7.53 (m, 2H), 7.15 (s, 1H),7.05 (d, J=8.3 Hz, 1H), 6.94 (dd, J=8.4, 2.1 Hz, 1H), 6.88 (d, J=2.0 Hz,1H), 5.79-5.67 (m, 2H), 5.18 (s, 1H), 4.30 (d, J=7.7 Hz, 1H), 4.22 (d,J=16.7 Hz, 2H), 4.14 (d, J=12.0 Hz, 2H), 4.02 (d, J=11.3 Hz, 2H),3.84-3.74 (m, 2H), 3.54-3.43 (m, 4H), 3.19 (m, 2H), 2.83-2.72 (m, 1H),2.41 (s, 1H), 2.04 (dd, J=10.7, 6.1 Hz, 2H), 2.00-1.80 (m, 6H), 1.54(dd, J=12.4, 3.9 Hz, 2H), 1.45 (s, 3H), 1.39 (s, 3H).

Example 306[(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]N-methoxy-N-methyl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 63 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 2 and N,O-dimethylhydroxylamine hydrochloride inStep 1. LCMS calc. for C₃₃H₄₁ClN₃O₉S [M+H]⁺: m/z=690.22/692.22; Found:690.0/692.0. ¹H NMR (300 MHz, CDCl₃) δ 9.05 (s, 1H), 7.56 (dd, J=8.4,2.0 Hz, 2H), 7.10 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.4, 0.9 Hz, 1H), 6.94(dd, J=8.5, 2.2 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 5.82-5.61 (m, 2H),5.35-5.17 (m, 1H), 4.30-3.99 (m, 5H), 3.77 (dd, J=14.7, 6.0 Hz, 2H),3.71 (s, 3H), 3.51-3.30 (m, 3H), 3.19 (s, 3H), 2.80 (d, J=7.9 Hz, 1H),2.47 (tt, J=8.9, 4.9 Hz, 1H), 2.01-1.81 (m, 4H), 1.66 (q, J=9.6 Hz, 2H),1.45 (s, 3H), 1.38 (s, 3H).

Example 307[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N-[2-(dimethylamino)ethyl]-N-methyl-carbamate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 1 and N,N,N′-trimethylethylenediamine in Step 2.LCMS calc. for C₃₆H₄₉ClN₄O₈S [M+H]⁺: m/z=731.28/733.28; Found:731.2/733.3. ¹H NMR (300 MHz, CDCl₃) δ 7.57 (d, J=8.4 Hz, 2H), 7.04 (d,J=8.1 Hz, 2H), 6.95 (dd, J=8.3, 1.9 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H),5.80 (d, J=37.2 Hz, 2H), 5.26 (s, 1H), 4.32 (s, 1H), 4.25-4.17 (m, 2H),4.13 (d, J=12.2 Hz, 2H), 3.79 (d, J=14.5 Hz, 2H), 3.44 (d, J=14.7 Hz,2H), 3.26 (s, 2H), 3.02 (s, 3H), 2.94 (s, 4H), 2.51-2.34 (m, 2H), 2.05(d, J=8.3 Hz, 2H), 1.97-1.77 (m, 4H), 1.65 (s, 2H), 1.47 (m, 3H), 1.37(s, 3H), 1.28 (s, 3H).

Example 308[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-ethoxypyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 1 and (3R)-3-ethoxypyrrolidine in Step 2. LCMScalc. for C₃₇H₄₇ClN₃O₉S [M+H]⁺: m/z=744.26/746.26; Found: 744.15/746.26;¹H NMR (300 MHz, CDCl₃) δ 9.49-9.09 (m, 1H), 7.55 (dd, J=8.4, 3.0 Hz,2H), 7.02 (d, J=6.3 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.86 (d, J=1.9 Hz,1H), 5.82 (d, J=14.2 Hz, 1H), 5.73-5.62 (m, 1H), 5.27 (s, 1H), 4.29 (d,J=10.0 Hz, 1H), 4.25-4.15 (m, 2H), 4.08 (dd, J=16.0, 9.3 Hz, 3H),3.82-3.72 (m, 2H), 3.71-3.61 (m, 4H), 3.42 (dd, J=13.4, 5.8 Hz, 4H),3.25-3.17 (m, 1H), 2.83 (s, 1H), 2.38 (d, J=8.2 Hz, 1H), 2.13-1.98 (m,4H), 1.86 (dd, J=14.6, 5.6 Hz, 3H), 1.67-1.60 (m, 1H), 1.45 (s, 3H),1.35 (s, 3H), 1.29-1.22 (m, 3H).

Example 309[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-methoxyazetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 1 and 3-methoxyazetidine in Step 2. LCMS calc. forC₃₅H₄₃ClN₃O₉S [M+H]⁺: m/z=716.23/718.23; Found: 716.2/718.3. ¹H NMR (300MHz, CDCl₃) δ 9.12 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.3 Hz,2H), 6.93 (dd, J=8.5, 2.0 Hz, 1H), 6.86 (d, J=1.9 Hz, 1H), 5.79 (d,J=15.5 Hz, 1H), 5.70-5.60 (m, 1H), 5.21 (s, 1H), 4.31-4.27 (m, 1H), 4.20(d, J=8.4 Hz, 3H), 4.13 (s, 1H), 4.10-4.01 (m, 2H), 3.91 (d, J=6.8 Hz,1H), 3.75 (t, J=12.1 Hz, 2H), 3.42 (s, 2H), 3.38 (s, 1H), 3.31 (s, 3H),3.22 (dd, J=14.9, 8.9 Hz, 2H), 2.79 (d, J=6.1 Hz, 1H), 2.37 (d, J=5.7Hz, 1H), 2.09-1.98 (m, 2H), 1.95-1.78 (m, 3H), 1.68-1.59 (m, 1H), 1.45(s, 3H), 1.36 (s, 3H).

Example 310[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl](3R)-3-(dimethylamino)pyrrolidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 1 and (3R)—N,N-dimethylpyrrolidin-3-amine in Step2. LCMS calc. for C₃₇H₄₈ClN₄O₈S [M+H]⁺: m/z=743.28/745.28; Found:743.2/745.2. ¹H NMR (300 MHz, CDCl₃) δ 9.20 (s, 1H), 7.53 (dd, J=16.3,8.7 Hz, 2H), 7.03 (d, J=8.3 Hz, 1H), 6.97-6.88 (m, 2H), 6.86 (d, J=2.0Hz, 1H), 6.00-5.73 (m, 2H), 5.30 (s, 1H), 4.33 (d, J=11.4 Hz, 1H),4.29-4.13 (m, 4H), 4.09 (d, J=12.0 Hz, 1H), 3.88 (d, J=14.8 Hz, 1H),3.75 (d, J=12.1 Hz, 3H), 3.63 (s, 2H), 3.44 (d, J=14.7 Hz, 2H),3.17-3.06 (m, 1H), 2.87 (d, J=18.8 Hz, 7H), 2.45-2.24 (m, 3H), 2.18 (s,1H), 2.02 (d, J=14.3 Hz, 1H), 1.88 (s, 3H), 1.71-1.62 (m, 1H), 1.44 (s,3H), 1.35 (s, 3H).

Example 311[(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]3-(dimethylamino)azetidine-1-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 46 Step 1-2 using(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(Example 246) in Step 1 and N,N-dimethylazetidin-3-amine dihydrochloridesalt and Hunig's base in Step 2. LCMS calc. for C₃₆H₄₆ClN₄O₈S [M+H]⁺:m/z=729.26/731.26; Found:729.2/731.5. ¹H NMR (300 MHz, CDCl₃) δ 7.53(dd, J=18.2, 10.3 Hz, 2H), 7.02 (d, J=8.2 Hz, 1H), 6.97-6.89 (m, 2H),6.86 (d, J=1.7 Hz, 1H), 6.10 (s, 1H), 5.71 (s, 1H), 5.30 (s, 1H), 4.34(d, J=11.2 Hz, 2H), 4.26 (d, J=12.1 Hz, 2H), 4.20 (d, J=10.9 Hz, 2H),4.07 (d, J=12.0 Hz, 1H), 3.80 (d, J=14.7 Hz, 2H), 3.73 (s, 2H), 3.43 (d,J=14.4 Hz, 2H), 3.02 (s, 2H), 2.83 (s, 6H), 2.27 (s, 1H), 2.02 (d,J=14.1 Hz, 2H), 1.85 (s, 3H), 1.65 (d, J=9.2 Hz, 2H), 1.36 (s, 3H), 1.27(s, 3H).

Example 312[(3R,6R,7S,8E,22S)-6′-Chloro-10,10-dideuterio-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

Step 1: 2-(1,1-dideuterioallyloxy)-2-methyl-propanoic acid

A suspension of lithium aluminium deuteride (2.0 g, 46.5 mmol) in ether(20 mL) was cooled at −78° C. under N₂. 2-Propenoyl chloride (4.0 mL,39.44 mmol) in ether (20 mL) was added dropwise over 1 h. at −78° C. Themixture was then allowed to slowly warm to r.t. and stirred overnight.The mixture was carefully quenched at −10° C. with water (4 mL),followed by 15% NaOH (4 mL). The mixture was diluted with water (12 mL),and stirred for 1 h. The mixture was filtered. The filtrate was driedover Na₂SO₄, filtered and the solvent was partially removed underreduced pressure. The crude product (0.25 g, 4.19 mmol) and2-bromo-2-methyl-propanoic acid (1.0 g, 5.99 mmol) was dissolved in MeCN(3 mL). DIPEA (2.3 g, 18 mmol) was added and the mixture was stirred at50° C. overnight. The mixture was quenched with 1 M HCl (20 mL) andextracted with EtOAc (20 mL×2). The organic layer was concentrated. Theresidue was purified with flash chromatography on a silica gel columnwith EtOAc:Heptane (0% to 40%) to afford2-(1,1-dideuterioallyloxy)-2-methyl-propanoic acid (500 mg, 40.% yield).

Step 2:(3R,6R,7S,8E,22S)-6′-Chloro-10,10-dideuterio-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[1,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one

This compound was prepared using procedures analogous to those describedfor Example 32 Step 1-2 using2-(1,1-dideuterioallyloxy)-2-methyl-propanoic acid to replace2-allyloxy-2-methyl-propanoic acid in Step 1. LCMS calc. forC₃₁H₃₆D2ClN₂O₆S [M+H]⁺: m/z=603.23/604.23; Found: 602.9.1/604.4.

Step 3:[(3R,6R,7S,8E,22S)-6′-Chloro-10,10-dideuterio-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate

This compound was prepared using procedures analogous to those describedfor Example 34. LCMS calc. for C₃₄H₄₁D2ClN₃O₇S [M+H]⁺:m/z=674.26/675.26; Found: 674.1/675.4.

Example 313(3R,6R,7S,8E,22S)-7′-chloro-7-[2-(dimethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one

Step 1:(3R,6R,7S,8E,22S)-7-(2-bromoethoxy)-7′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,4′-chromane]-13-one

To a solution of(3R,6R,7S,8E,22S)-7′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,4′-chromane]-13-one(130 mg, 0.22 mmol, Example 246) in toluene (4 mL) was added2,6-ditert-butylpyridine (412 mg, 2.2 mmol) followed by 2-bromoethyltrifluoromethanesulfonate (554 mg, 2.2 mmol). The resulting mixture wasstirred at 90° C. overnight. The reaction was quenched with 1N HCl aq.solution (1 mL) and extracted with EtOAc. The combined organic extractswere washed with water and brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by flash chromatographyon a silica gel column with EtOAc/Heptanes (3% to 60%) to afford(3R,6R,7S,8E,22S)-7-(2-bromoethoxy)-7′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,4′-chromane]-13-one(105 mg, 68.6% yield) as a white solid. LC-MS: calc. for C₃₂H₃₉BrClN₂O₇S[M+H]⁺: m/z=709.1/711.1; Found: 709.0/710.8.

Step 2.(3R,6R,7S,8E,22S)-7′-chloro-7-[2-(dimethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one

To a stirred solution of(3R,6R,7S,8E,22S)-7-(2-bromoethoxy)-7′-chloro-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,4′-chromane]-13-one(30 mg, 0.04 mmol) in DMSO (1 mL) was added potassium iodide (35 mg,0.21 mmol) and dimethylamine (2 M in THF) (9.5 mg, 0.21 mmol). Theresulting solution was stirred at 35° C. for 1 h. The reaction mixturewas directly purified by prep-HPLC on C18 column (30×250 mm, 10 m) withMeOH/H₂O (15% to 100%) to afford(3R,6R,7S,8E,22S)-7′-chloro-7-[2-(dimethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one(11 mg, 38.6% yield) as a white solid. LC-MS calc. for C₃₄H₄₅ClN₃O₇S[M+H]⁺: m/z=674.26/676.26; Found: 674.2/676.4.

Example 314(3R,6R,7S,8E,22S)-7′-chloro-7-[2-(diethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one

This compound was prepared using procedures analogous to those describedfor Example 313 Step 2 using diethylamine (2 M in THF) to replacedimethylamine (2 M in THF). LC-MS calc. for C₃₆H₄₉ClN₃O₇S [M+H]⁺:m/z=702.29/704.29; Found: 702.0/703.5.

Example 315(3R,6R,7S,8E,22S)-7′-chloro-12,12-dimethyl-15,15-dioxo-7-(2-pyrrolidin-1-ylethoxy)spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one

This compound was prepared using procedures analogous to those describedfor Example 313 Step 2 using pyrrolidine to replace dimethylamine (2 Min THF). LC-MS calc. for C₃₆H₄₇ClN₃O₇S [M+H]⁺: m/z=700.27/702.27; Found:700.2/702.6. Single-Crystal X-ray Analysis of Example 34

A saturated solution of Example 34 in ethanol/methyl tert-butyl ether(4/1) was stored at 23-25° C., and after 4 days, cubic crystals wereobserved. A crystal of approximate dimensions 0.197 mm×0.250 mm×0.345mm, was used for the X-ray crystallographic analysis. The X-rayintensity data were measured.

The total exposure time was 3.45 hours. The frames were integrated withthe Bruker SAINT software package using a narrow-frame algorithm. Theintegration of the data using an orthorhombic unit cell yielded a totalof 26210 reflections to a maximum 0 angle of 75.550 (0.80 Å resolution),of which 8525 were independent (average redundancy 3.074,completeness=98.9%, R_(int)=4.77%, R_(sig)=4.89%) and 7840 (91.96%) weregreater than 2σ(F²). The final cell constants of a=9.1529(13) Å,b=11.1812(17) Å, c=41.054(7) Å, volume=4201.5(11) Å³, are based upon therefinement of the XYZ-centroids of 9678 reflections above 20 σ(I) with6.463°<2θ<150.8°. Data were corrected for absorption effects using theMulti-Scan method (SADABS). The ratio of minimum to maximum apparenttransmission was 0.838. The calculated minimum and maximum transmissioncoefficients (based on crystal size) are 0.5830 and 0.7240.

FIG. 1 shows an ORTEP representation of the compound of Example 34. Thestructure was solved and refined using the Bruker SHELXTL SoftwarePackage, using the space group P 21 21 21, with Z=4 for the formulaunit, C₄₀H₆₀ClN₃O₁₀S. The final anisotropic full-matrix least-squaresrefinement on F² with 504 variables converged at R¹=7.06%, for theobserved data and wR2=20.53% for all data. The goodness-of-fit was1.151. The largest peak in the final difference electron densitysynthesis was 0.445 e⁻/Å³ and the largest hole was −0.447 e⁻/Å³ with anRMS deviation of 0.091 e⁻/Å³. On the basis of the final model, thecalculated density was 1.281 g/cm³ and F (000), 1736 e⁻.

TABLE E1 Sample and crystal data for Example 34. Identification codeExample 34 Chemical formula C₄₀H₆₀ClN₃O₁₀S (includes 3 ethanols) Formulaweight 810.42 g/mol Temperature 150(2) K Wavelength 1.54178 Å Crystalsize 0.197 × 0.250 × 0.345 mm Crystal system orthorhombic Space group P21 21 21 Unit cell dimensions a = 9.1529(13) Å α = 90° b = 11.1812(17) Åβ = 90° c = 41.054(7) Å γ = 90° Volume 4201.5(11) Å³ Z 4 Density(calculated) 1.281 g/cm³ Absorption 1.752 mm⁻¹ coefficient F(000) 1736

TABLE E2 Data collection and structure refinement for Example 34. Thetarange for 2.15 to 75.55° data collection Index ranges −11 <= h <= 11,−13 <= k <= 13, −51 <= l <= 51 Reflections 26210 collected Independent8525 [R(int) = 0.0477] reflections Coverage of 98.9% independentreflections Absorption correction Multi-Scan Max. and min. 0.7240 and0.5830 transmission Structure solution direct methods techniqueStructure solution XT, VERSION 2014/5 program Refinement methodFull-matrix least-squares on F² Refinement program SHELXL-2018/3(Sheldrick, 2018) Function minimized Σ w(F_(o) ² − F_(c) ²)²Data/restraints/ 8525/0/504 parameters Goodness-of-fit 1.151 on F²Δ/σ_(max) 0.001 Final R indices 7840 data; I > 2σ(I) R1 = 0.0706, wR2 =0.2010 all data R1 = 0.0740, wR2 = 0.2053 Weighting scheme w =1/[σ²(F_(o) ²) + (0.1199P)² + 1.8325P] where P = (F_(o) ² + 2F_(c) ²)/3Absolute structure 0.002 (11) parameter Extinction 0.0048(6) coefficientLargest diff. 0.445 and −0.447 eÅ⁻³ peak and hole R.M.S. deviation 0.091eÅ⁻³ from mean Biological Assays Cell free Mcl-1: Bim affinity assay(Mcl-1 Bim)

The binding affinity of each compound was measured via a fluorescencepolarization competition assay, in which the compound competes for thesame binding site with the ligand, and thus leads to a dose-dependentanisotropy reduction. The tracer ligand utilized was a fluoresceinisothiocyanate labelled peptide (FITC-ARIAQELRRIGDEFNETYTR) derived fromBim (GenScript).

The assay was carried out in black half-area 96-well NBS plate(Corning), containing 15 nM of MCL-1 (BPS Bioscience), 5 nM of FITC-Bimand 3-fold serial diluted test compounds in a total volume of 50 μL ofassay buffer (20 mM HEPES, 50 mM NaCl, 0.002% Tween 20, 1 mM TCEP, and1% DMSO). The reaction plate was incubated for 1 hour at roomtemperature. The change of anisotropy is measured with an Envisionmultimode plate reader (PerkinElmer) at emission wavelength 535 nm.Fluorescence polarization was calculated in mP unit and the percentageinhibition was calculated by % inhibition=100×(mPDMSO-mP)/(mPDMSO-mPPc),in which mPDMSO is the DMSO control, and mPPc is the positive control.IC₅₀ values were determined from a 10-point dose response curve byfitting the percent inhibition against compound concentration using theGraphPad Prism software. The inhibition constant K_(i) was subsequentlycalculated according to the Nikolovska-Coleska's equation (Anal.Biochem., 2004, 332, 261),

$K_{i} = \frac{\lbrack I\rbrack_{50}}{\frac{\lbrack L\rbrack_{50}}{K_{d}} + \frac{\lbrack P\rbrack_{0}}{K_{d}} + 1}$

-   -   where [I]₅₀ is the concentration of the free inhibitor at 50%        inhibition, [L]₅₀ is the concentration of the free labeled        ligand at 50% inhibition, [P]₀ is the concentration of the free        protein at 0% inhibition, and K_(d) is the dissociation constant        of the protein-ligand complex. See Table F.

Caspase 3/7 Activity Assay

Dispense 10 μL aliquot of prepared H929 cells (1:1 ratio of cells:TrypanBlue (#1450013, Bio-Rad)) onto cell counting slide (#145-0011, Bio-Rad)and obtain cell density and cell viability using cell counter (TC20,Bio-Rad). Remove appropriate volume of resuspended cells from cultureflask to accommodate 2000 cells/well @ 5 μL/well. Transfer H929 cells to50 mL conical (#430290, Corning) for each of the FBS concentration to beassayed (10%, 0.1%). Spin down at 1000 rpm for 5 min. using tabletopcentrifuge (SPINCHRON 15, Beckman). Discard supernatant and resuspendcell pellet in modified RPMI 1640 (#10-040-CV, Corning) cell culturemedia containing sodium pyruvate (100 mM) (#25-000-CL, Corning), HEPESbuffer (1 M) (#25-060-CL, Corning) and glucose (200 g/L) (A24940-01,Gibco) with appropriate FBS (F2422-500 ML, Sigma) concentration to acell density of 400,000 cells/mL. Dispense 5 μL of resuspended H929cells per well in 384-well small volume TC treated plate (#784080,Greiner Bio-one) using standard cassette (#50950372, Thermo Scientific)on Multidrop Combi (#5840310, Thermo Scientific) in laminar flowcabinet. Dispense compounds onto plates using digital liquid dispenser(D300E, Tecan). Incubate plates in humidified tissue culture incubator @37° C. for 4 hours. Add 5 μL of prepared Caspase-Glo® 3/7 detectionbuffer (G8093, Promega) to each well of 384-well plate using small tubecassette (#24073295, Thermo Scientific) on Combi multi-drop, incubate @RT for 30-60 min. Read plates with microplate reader (PheraStar, BMGLabtech) using 384 well luminescence mode.

Cell Viability Assay (H929 10 FBS)

Dispense 10 μL aliquot of prepared H929 cells (1:1 ratio of cells:TrypanBlue (#1450013, Bio-Rad)) onto cell counting slide (#145-0011, Bio-Rad)and obtain cell density and cell viability using cell counter (TC20,Bio-Rad). Remove appropriate volume of resuspended cells from cultureflask to accommodate 4000 cells/well @ 10 μL/well. Transfer H929 cellsto 50 mL conical (#430290, Corning). Spin down at 1000 rpm for 5 minusing tabletop centrifuge (SPINCHRON 15, Beckman). Discard supernatantand resuspend cell pellet in modified RPMI 1640 (#10-040-CV, Corning)cell culture media containing 10% FBS (F2422-500 ML, Sigma), sodiumpyruvate (100 mM) (#25-000-CL, Corning), HEPES buffer (1 M) (#25-060-CL,Corning) and glucose (200 g/L) (A24940-01, Gibco) to a cell density of400,000 cells/mL. Dispense 10 μL of resuspended H929 cells per well in384-well small volume TC treated plate (#784080, Greiner Bio-one) usingstandard cassette (#50950372, Thermo Scientific) on Multi-drop Combi(#5840310, Thermo Scientific) in laminar flow cabinet. Dispensecompounds onto plates using digital liquid dispenser (D300E, Tecan).Incubate plates in humidified tissue culture incubator @ 37° C. for 24hours. Add 10 μL of prepared CellTiTer-Glo® detection buffer (G7570,Promega) or ATPlite 1 Step detection reagent (#6016731, Perkin Elmer) toeach well of 384-well plate using small tube cassette (#24073295, ThermoScientific) on Combi multi drop, incubate @ RT for 30-60 min. Readplates with microplate reader (PheraStar, BMG Labtech) using 384 wellluminescence mode.

Cytotoxicity Studies in NCI-H929 Cells

Cytotoxicity studies were conducted in NCI-H929 multiple myeloma cellline. Cells were maintained in RPMI 1640 (Corning Cellgro, Catalog #:10-040-CV) supplemented with 10% v/v FBS (GE Healthcare, Catalog #:SH30910.03), 10 mM HEPES (Corning, Catalog #: 25-060-CI), 1 mM sodiumpyruvate (Corning Cellgro, Catalog #: 25-000-CI and 2500 mg/L glucose(Gibco, Catalog #: A24940-01). Cells were seeded in 96-well plates at adensity of 75000 cells/well. Compounds dissolved in DMSO were plated induplicate using a digital dispenser (Tecan D300E) and tested on a9-point 3-fold serial dilution. Cells were incubated for 24 hr in a 37°C. incubator at 5% CO₂. Cell viability was measured using the CellCounting Kit-8 (CCK-8, Jojindo, CK04-13) as per manufacturer'sinstructions. Cells were incubated for 4 hours at 37° C. 5% CO₂following addition of reagent and OD₄₅₀ values were measured with amicroplate reader (iMark microplate reader, Bio-Rad). Background frommedia only wells were averaged and subtracted from all readings. OD₄₅₀values were then normalized to DMSO controls to obtain percentage ofviable cells, relative to DMSO vehicle control and plotted in GraphpadPrism ([Inhibitor] vs. normalized response—Variable slope; equation:Y=100/(1+(X{circumflex over ( )}HillSlope)/(IC₅₀{circumflex over( )}HillSlope))) to determine IC₅₀ values (the concentration of compoundinhibiting half of the maximal activity).

TABLE F Cell free Mcl-1: Bim affinity assay (Mcl-1 Bim) and Cellviability assay (H929_10FBS) Ex BIM_Ki H929_10FBS IC₅₀ No. (nM) (nM) 145.6 # 2 179 # 3 143 # 4 207 # 5 37.3 # 6 35.7 # 7 227 NT 8 424 # 9 1640# 10 1430 # 11 503 # 12 15.8 # 13 22 # 14 222 NT 15 8.7 # 16 9 # 17 7.4# 18 1.4 # 19 9.3 # 20 21.8 # 21 53.3 # 22 57 # 23 73.6 # 24 6.0 # 259.0 # 26 ++ # 27 ++ # 28 +++ # 29 +++ ## 30 +++ ## 31 ++ # 32 +++ ### 33+++ ### 34 +++ ### 35 ++ # 36 +++ ## 37 +++ ### 38 +++ ### 39 +++ ## 40+++ ### 41 +++ ### 42 ++ ### 43 ++ # 44 +++ ### 45 +++ ### 46 +++ ### 47+++ ### 48 +++ ### 49 +++ ### 50 +++ ### 51 +++ ### 52 +++ ### 53 +++### 54 +++ ### 55 +++ ### 56 +++ ### 57 +++ ### 58 +++ ### 59 +++ ### 60+++ ### 61 +++ ### 62 +++ ### 63 +++ ### 64 +++ ### 65 +++ ### 66 +++### 67 ++ # 68 ++ # 69 ++ # 70 ++ # 71 ++ # 72 ++ # 73 ++ # 74 +++ # 75++ # 76 ++ # 77 ++ # 78 ++ # 79 ++ # 80 ++ # 81 ++ # 82 ++ # 83 ++ # 84++ # 85 ++ # 86 ++ # 87 +++ ## 88 +++ ## 89 ++ # 90 +++ # 91 ++ # 92 +++## 93 ++ # 94 +++ # 95 ++ # 96 +++ # 97 +++ # 98 ++ # 99 ++ # 100 ++ #101 +++ # 102 ++ # 103 +++ # 104 +++ # 105 ++ # 106 ++ ## 107 ++ ## 108++ # 109 ++ # 110 ++ # 111 ++ # 112 ++ # 113 +++ ## 114 +++ ## 115 ++ #116 ++ ## 117 ++ # 118 ++ # 119 ++ ## 120 ++ ## 121 ++ # 122 ++ # 123 ++## 124 ++ ## 125 +++ # 126 ++ # 127 ++ ## 128 ++ # 129 ++ # 130 ++ # 131++ # 132 ++ ### 133 ++ # 134 ++ # 135 ++ # 136 ++ # 137 ++ ## 138 ++ ##139 ++ ## 140 +++ ### 141 +++ ### 142 +++ ## 143 +++ ### 144 ++ # 145+++ ### 146 ++ ### 147 +++ ### 148 +++ ### 149 +++ ### 150 +++ ## 151+++ ### 152 +++ ### 153 +++ ### 154 +++ ### 155 +++ ### 156 +++ ### 157+++ ### 158 +++ ### 159 +++ ### 160 +++ ### 161 +++ ## 162 +++ ### 163+++ ### 164 +++ ### 165 +++ ### 166 +++ ### 167 +++ ### 168 +++ ### 169+++ ### 170 +++ ## 171 +++ ### 172 +++ ### 173 +++ ### 174 +++ ### 175+++ ### 176 +++ ### 177 ++ ### 178 +++ ### 179 +++ ### 180 +++ ### 181+++ ### 182 +++ ### 183 +++ ### 184 +++ ### 185 +++ ### 186 +++ ### 187+++ ### 188 +++ ### 189 +++ ### 190 +++ ### 191 +++ ### 192 +++ ### 193++ ### 194 +++ ### 195 +++ ### 196 ++ # 197 ++ # 198 +++ ### 199 +++ ###200 ++ ### 201 +++ ### 202 +++ ### 203 +++ ### 204 +++ ### 205 ++ ###206 +++ ### 207 +++ ### 208 ++ ### 209 +++ ### 210 +++ ### 211 +++ ###212 +++ ### 213 +++ ### 214 +++ ### 215 +++ ### 216 +++ ### 217 +++ ###218 +++ ### 219 ++ ### 220 +++ ### 221 +++ ### 222 +++ ### 223 +++ ###224 +++ ### 225 ++ ### 226 +++ ### 227 +++ ### 228 +++ ### 229 +++ ###230 +++ ### 231 +++ ### 232 +++ ### 233 +++ ### 234 +++ ### 235 +++ ###236 +++ ### 237 +++ ### 238 +++ ### 239 +++ ### 240 +++ ### 241 +++ ###242 +++ ### 243 +++ ### 244 +++ ### 245 +++ ### 246 ++ # 247 +++ ### 248+++ # 249 ++ # 250 +++ ### 251 ++ # 252 ++ # 253 ++ # 254 ++ # 255 ++ #256 ++ # 257 ++ # 258 +++ ### 259 +++ ### 260 +++ ### 261 +++ ### 262+++ ### 263 +++ ### 264 +++ ### 265 ++ ### 266 +++ ### 267 ++ ## 268 +++### 269 +++ ### 270 +++ ### 271 +++ ### 272 +++ ### 273 +++ ## 274 +++## 275 ++ ### 276 +++ ## 277 ++ # 278 +++ ### 279 +++ ### 280 +++ ###281 +++ ### 282 +++ ### 283 +++ ### 284 +++ ### 285 +++ ### 286 ++ # 287+++ ### 288 ++ # 289 ++ # 290 +++ ### 291 +++ ## 292 +++ ### 293 +++ ###294 ++ ### 295 ++ # 296 ++ ### 297 ++ # 298 +++ ## 299 +++ ## 300 +++ ##301 +++ ### 302 +++ ### 303 +++ ### 304 +++ ### 305 +++ ### 306 +++ ###307 +++ ### 308 +++ ### 309 +++ ## 310 +++ ### 311 +++ ### 312 +++ ###313 NT NT 314 NT NT 315 NT NT +++ K_(i) < 1 nM; ++ K_(i) = 1 nM-100 nM;### IC₅₀ < 500 nM; ## IC₅₀ < 1000 nM; # IC₅₀ > 1000 nM; NT = not tested

In some embodiments, the invention is directed to the following aspects:

-   Aspect 1. A compound of Formula I:

-   -   or a pharmaceutically acceptable salt or solvate thereof;    -   wherein    -   Z is CH or N;    -   Q is —O—, —S—, —S(O)—, or —S(O)₂—;    -   the moiety -W¹-W²-W³ is —CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—,        —O—CR^(2B)R^(2C)—CR²R^(2A)—, —CR²R^(2A)—CR^(2B)R^(2C)—O—,        —NR^(2B)—CR^(2B)R^(2C)—CR²R^(2A)—, —CR²R^(2A)—CR^(2B)R^(2C)—        NR^(2B)—, —S—CR^(2B)R^(2C)—CR²R^(2A), or        —CR²R^(2A)—CR^(2B)R^(2C)—S—;    -   L¹ is absent or is optionally substituted —C₁-C₆alkylene-;    -   L² is absent or is optionally substituted cycloalkylene,        optionally substituted heterocycloalkylene, optionally        substituted arylene, or optionally substituted heteroarylene;    -   L³ is absent, or is —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—, —C(═O)O—,        —NR^(6A)C(O)—, —C(═O)NR^(6A)—, —OC(═O)N(R^(6A))—,        —NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—,        or —NR^(6A)S(O)₂—;    -   L⁴ is absent, or is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is        absent, —CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—,        —NR⁶—, —OC(═O)—, —C(═O)O—, —NR^(6A)C(O)—, —C(═O)NR^(6A)—,        —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—,        —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or        —NR^(6A)S(O)₂—; or is        —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—;    -   L⁵ is absent, or is —C₁-C₆ alkylene-, —C₂-C₆ alkenylene-, —C₂-C₆        alkynylene-, -arylene-, -heteroarylene-, -cycloalkenylene-,        -cycloalkylene-, -heterocycloalkylene-, wherein said C₁-C₆        alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, arylene,        heteroarylene, cycloalkenylene, cycloalkylene, or        heterocycloalkylene groups are optionally substituted;    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—, —(CR⁷R⁸)_(s)O(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t)—, —(CR⁷R⁸)_(s)S(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t)—, —(CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)NR^(9A)C(O)(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)OC(O)NR^(9A)(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)SNR^(9A)C(O)O(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)SNR^(9A)S(O)(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)NR^(9A)S(O)₂(CR⁷R⁸)_(t)—;        —(CR⁷R⁸)_(s)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—,        —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—; —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—,        or —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—;    -   each n is independently 0-3;    -   each m is independently 0-2;    -   each p is independently 0-4;    -   each q is independently 0-4;    -   each s is independently 0-3;    -   each t is independently 0-4;    -   each R is independently -D, -halo, —CN, —NO₂, —C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₁-C₆alkoxy, -cycloalkyl, —OR^(a), —SR^(a),        —C(O)R^(b), —C(O)OR^(a), —NR^(c)R^(d), —C(O)NR^(c)R^(d), or        —S(O)₂R^(a); wherein said —C₁-C₆alkyl, —C₂-C₆alkenyl,        —C₁-C₆alkoxy, or -cycloalkyl is optionally substituted;    -   each R¹ is independently -D, -halo, —CN, —NO₂, —C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OR^(a), —SR^(a), —NR^(c)R^(d),        —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(a), —C(O)NR^(c)R^(d),        —S(O)₂R^(a); -aryl, -heteroaryl, -cycloalkyl, or        -heterocycloalkyl, wherein said —C₁-C₆alkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, -cycloalkyl, -heterocycloalkyl, -aryl, or        -heteroaryl is optionally substituted;    -   each R², R^(2A), or R^(2a) is independently H, D, halo, OR^(a),        optionally substituted C₁-C₆alkyl, or R² and R^(2A) that are        attached to the same carbon atom may, together with the carbon        atom to which they are both attached, form an optionally        substituted cycloalkyl ring;    -   each R^(2B) and R^(2C) is independently H, D, optionally        substituted C₁-C₆alkyl, or R^(2B) and R^(2C) may, together with        the carbon atom to which they are both attached, form an        optionally substituted cycloalkyl ring;    -   R³ is H, D, —C₁-C₆alkyl, —C₃-C₆alkenyl, —C₃-C₆alkynyl,        cycloalkyl, heterocycloalkyl, C(O)R^(b), C(O)OR^(a), or        C(O)NR^(c)R^(d); wherein said C₁-C₆alkyl, —C₃-C₆alkenyl,        —C₃-C₆alkynyl, cycloalkyl, or heterocycloalkyl is optionally        substituted; or R³ is —C₁-C₆alkyl substituted at the C₁ carbon        atom with —OR^(3A) wherein R^(3A) is C₁-C₆alkyl, —PO₃H,        —C(O)OR^(2C), or —C(O)NR^(3A)R^(3B) wherein R^(3A) and R^(3B)        are each independently H, D, optionally substituted C₁-C₆alkyl;    -   each R⁴ or R⁷ is independently H, D, halo, —OH, —CN, —NO₂,        —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl, —OR^(a), —SR^(a), —NR^(c)R^(d),        —NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(a), —C(O)OR^(a),        —C(O)NR^(c)R^(d), —S(O)R^(b), or —S(O)₂R^(b), wherein said        C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkenyl, or        heterocycloalkyl is optionally substituted;    -   each R^(4A) or R^(4B) is independently H, D, -Me, —CF₃ or —F;    -   each R⁵ or R⁸ is independently H, D, fluoro, —C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C(O)R^(b), —C(O)OR^(a),        —C(O)NR^(c)R^(d), aryl, heteroaryl, cycloalkyl, cycloalkenyl,        heterocycloalkyl, or heterocycloalkenyl, wherein said        C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl is optionally substituted;    -   or R⁴ and R⁵ together with the C atom to which they are attached        form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl ring, each optionally substituted;    -   or an R⁴ and an R⁵ attached to adjacent carbon atoms, together        with the C atoms to which they are attached, form a cycloalkyl,        cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each        optionally substituted;    -   or R⁷ and R⁸ together with the C atom to which they are both        attached form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl ring, each optionally substituted, each        optionally substituted;    -   or an R⁷ and an R⁸ attached to adjacent carbon atoms, together        with the C atoms to which they are attached, form a cycloalkyl,        cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each        optionally substituted;    -   each R⁶ or R⁹ is independently H, D, —C₁-C₆alkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, —OC₁-C₆alkyl, —C(O)R^(b), —C(O)OR^(a),        —C(O)NR^(c)R^(d), —S(O)R^(b) or —S(O)₂R^(b), aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl group, wherein said C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OC₁-C₆alkyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl ring, is optionally substituted;    -   or R⁹ together with either an R⁷ or an R⁸ forms an optionally        substituted heterocyclic alkylene;    -   each R^(6A), R^(6B), R^(9A), or R^(9B) is independently H, D,        —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, cycloalkyl,        cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein        said C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, cycloalkyl,        cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is        optionally substituted;    -   or R^(6A) and R^(6B) together with the N atoms to which they are        attached form an optionally substituted heterocycloalkyl or        heterocycloalkenyl ring;    -   or R^(9A) and R^(9B) together with the N atoms to which they are        attached form an optionally substituted heterocycloalkyl or        heterocycloalkenyl ring;    -   each R^(a) is independently H, D, —C(O)R^(b), —C(O)OR^(c),        —C(O)NR^(c)R^(d), —P(OR^(c))₂, —P(O)R^(c)R^(b),        —P(O)OR^(c)OR^(b), —S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b),        —S(O)₂NR^(c)R^(d), —B(OR^(c))(OR^(b)), SiR^(b) ₃, —C₁-C₁₀alkyl,        —C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, aryl, cycloalkyl,        cycloalkenyl, heteroaryl, heterocycloalkyl, or        heterocycloalkenyl wherein said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,        heterocycloalkyl, or heterocycloalkenyl is optionally        substituted;    -   each R^(b), is independently H, D, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,        heterocycloalkyl, or heterocycloalkenyl wherein said —C₁-C₆        alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, aryl, cycloalkyl,        cycloalkeneyl, heteroaryl, heterocycloalkyl, or        heterocycloalkenyl is optionally substituted;    -   each R^(c) or R^(d) is independently H, D, —C₁-C₁₀ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl, wherein said C₁-C₁₀ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, —O_(C1)-C₆alkyl, —O-cycloalkyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl are each optionally substituted;    -   or R^(c) and R^(d), together with the N atom to which they are        both attached, form an optionally substituted monocyclic or        multicyclic heterocycloalkyl, or optionally substituted        monocyclic or multicyclic heterocycloalkenyl group.

-   Aspect 2. The compound according to aspect 1 having the Formula    IA-0,

-   -   or a pharmaceutically acceptable salt or solvate thereof;        wherein    -   Z is CH or N;    -   Q is —O—, —S—, —S(O)—, or —S(O)₂—;    -   the moiety -W¹-W²-W³ is —CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—,        —O—CR^(2B)R^(2C)—CR²R^(2A)—, —CR²R^(2A)—CR^(2B)R^(2C)—O—,        —NR^(2B)—CR^(2B)R^(2C)—CR²R^(2A)—, —CR²R^(2A)—CR^(2B)R^(2C)—        NR^(2B)—, —S—CR^(2B)R^(2C)—CR²R^(2A)—, or        —CR²R^(2A)—CR^(2B)R^(2C)—S—;    -   L¹ is optionally substituted —C₁-C₆alkylene-;    -   L² is optionally substituted 3-7 membered cycloalkylene,        optionally substituted 4-7 membered heterocycloalkylene,        optionally substituted arylene, or optionally substituted        heteroarylene;    -   L³ is absent, or is —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—, —C(═O)O—,        —NR^(6A)C(O)—, —C(═O)NR^(6A)—, —OC(═O)N(R^(6A))—,        —NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—,        or —NR^(6A)S(O)₂—;    -   L⁴ is absent, or is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is        absent, —CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—,        —NR⁶—, —OC(═O)—, —C(═O)O—, —NR^(6A)C(O)—, —C(═O)NR^(6A)—,        —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—,        —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or        —NR^(6A)S(O)₂—; or is        —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—;    -   L⁵ is absent, or is —C₁-C₆ alkylene-, —C₂-C₆ alkenylene-, —C₂-C₆        alkynylene-, a 6- to 10-membered arylene, 5- to 10-membered        heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to        7-membered monocyclic cycloalkylene, or 6- to 12 bicyclic        cycloalkylene, a 3- to 7-membered monocyclic        heterocycloalkylene, or 6- to 12-membered bicyclic        heterocycloalkylene group, wherein said C₁-C₆ alkylene, C₂-C₆        alkenylene, C₂-C₆ alkynylene, a 6- to 10-membered arylene, 5- to        10-membered heteroarylene, a 3- to 12-membered cycloalkenylene,        a 3- to 7-membered monocyclic cycloalkylene, or 6- to 12        bicyclic cycloalkylene, a 3- to 7-membered monocyclic        heterocycloalkylene, or 6- to 12-membered bicyclic        heterocycloalkylene groups are optionally substituted;    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—, —O(CR⁷R⁸)_(t)—,        —NR⁹(CR⁷R⁸)_(t)—, —S(CR⁷R⁸)_(t)—, —S(O)(CR⁷R⁸)_(t)—,        —S(O)₂(CR⁷R⁸)_(t)—, —NR^(9A)C(O)(CR⁷R⁸)_(t)—,        —C(O)NR^(9A)(CR⁷R⁸)_(t)—, —R^(9A)C(O)O(CR⁷R⁸)_(t)—,        —NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—, —NR^(9A)S(O)(CR⁷R⁸)_(t)—,        —NR^(9A)S(O)₂(CR⁷R⁸)_(t)—; —CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—,        —C(═O)(CR⁷R⁸)_(t)—; —C(═O)(CR⁷R⁸)_(t)—O—, or        —C(═O)(CR⁷R⁸)_(t)—NR⁶—;    -   each n is independently 0-3;    -   each m is independently 0-2;    -   each p is independently 0-4;    -   each q is independently 0-4;    -   each s is independently 0-3;    -   each t is independently 0-4;    -   each R is independently D, halo, —CN, —NO₂, C₁-C₆alkyl,        C₂-C₆alkenyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, —OR^(a), —SR^(a),        —C(O)R^(b), —C(O)OR^(a), —NR^(c)R^(d), —C(O)NR^(c)R^(d), or        —S(O)₂R^(a); wherein said C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkoxy,        or C₃-C₆cycloalkyl is optionally substituted;    -   each R¹ is independently D, halo, —CN, —NO₂, —C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OR^(a), —SR^(a), —NR^(c)R^(d),        —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(a), —C(O)NR^(c)R^(d),        —S(O)₂R^(a); aryl, heteroaryl, cycloalkyl, or heterocycloalkyl,        wherein said C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, is optionally        substituted;    -   each R², R^(2A), or R^(2a) is independently H, D, halo, —OR^(a),        optionally substituted —C₁-C₆alkyl, or R² and R^(2A), that are        attached to the same carbon atom may, together with the carbon        atom to which they are both attached, form an optionally        substituted 3-7 membered cycloalkyl ring;    -   R^(2B) and R^(2C) are each independently H, D, optionally        substituted C₁-C₆alkyl, or R^(2B) and R^(2C) may, together with        the carbon atom to which they are both attached, form an        optionally substituted 3-7 membered cycloalkyl ring;    -   R³ is H, D, —C₁-C₆alkyl, —C₃-C₆alkenyl, —C₃-C₆alkynyl, 3-7        membered cycloalkyl, -4-7 membered heterocycloalkyl, —C(O)R^(b),        —C(O)OR^(a), or —C(O)NR^(c)R^(d); wherein said C₁-C₆alkyl,        —C₃-C₆alkenyl, —C₃-C₆alkynyl, cycloalkyl, and heterocycloalkyl        is optionally substituted; or R³ is —C₁-C₆alkyl substituted at        the C₁ carbon atom with —OR^(3A) wherein R^(3A) is C₁-C₆alkyl,        —PO₃H, —C(O)OR^(2C), or —C(O)NR^(3A)R^(3B) wherein R^(3A) and        R^(3B) are each independently H, D, optionally substituted        C₁-C₆alkyl;    -   each R⁴ or R⁷ is independently H, D, halo, —OH, —CN, —NO₂,        —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, 3-7 membered        cycloalkyl, —OR^(a), —SR^(a), —NR^(c)R^(d), —NR^(a)R^(c),        —C(O)R^(b), —OC(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(d),        —S(O)R^(b), —S(O)₂R^(b), aryl, heteroaryl, or heterocycloalkyl,        wherein said C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl,        heteroaryl, cycloalkyl, or heterocycloalkyl is optionally        substituted;    -   each R^(4A) or R^(4B) is independently H, D, -Me, —CF₃ or —F;    -   each R⁵ or R⁸ is independently H, D, fluoro, —C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₂-C₆alkynyl, —C(O)R^(c), —C(O)OR^(c),        —C(O)NR^(c)R^(d), aryl, heteroaryl, cycloalkyl, or        heterocycloalkyl, wherein said C₁-C₆alkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl        is optionally substituted;    -   or R⁴ and R⁵ together with the C atom to which they are attached        form a cycloalkyl or heterocycloalkyl ring, each optionally        substituted;    -   or R⁷ and R⁸ together with the C atom to which they are attached        form a cycloalkyl or heterocycloalkyl ring, each optionally        substituted;    -   each R⁶ or R⁹ is independently H, D, —C₁-C₆alkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, —OC₁-C₆alkyl, —C(O)R^(b), —C(O)OR^(a),        —C(O)NR^(c)R^(d), —S(O)R^(b) or —S(O)₂R^(b), aryl, heteroaryl,        cycloalkyl, or heterocycloalkyl group, wherein said C₁-C₆alkyl,        —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OC₁-C₆alkyl, -aryl, heteroaryl,        cycloalkyl, or heterocycloalkyl is optionally substituted;    -   each R^(6A), R^(6B), R^(9A), or R^(9B) is independently H, D,        C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, 3-7 membered        cycloalkyl, 4-7 membered heterocycloalkyl, wherein said        C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, 3-7 membered        cycloalkyl, or 4-7 membered heterocycloalkyl is optionally        substituted;    -   or R^(6A) and R^(6B) together with the atoms to which they are        attached form an optionally substituted heterocycloalkyl ring;    -   or R^(9A) and R^(9B) together with the N atom to which they are        attached form an optionally substituted heterocycloalkyl ring;    -   each R^(a) is independently H, D, —C(O)R^(b), —C(O)OR^(e),        —C(O)NR^(c)R^(d), —P(OR^(c))₂, —P(O)R^(c)R^(b),        —P(O)OR^(c)OR^(b), —S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b),        —S(O)₂NR^(c)R^(d), —B(OR^(c))(OR^(b)), —SiR^(b)3, —C₁-C₁₀alkyl,        —C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, aryl, cycloalkyl, heteroaryl,        heterocycloalkyl, wherein said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, or        heterocycloalkyl is optionally substituted;    -   each R^(b) is independently H, D, C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,        wherein said C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,        cycloalkyl, heteroaryl, or heterocycloalkyl is optionally        substituted;    -   each R^(c) or R^(d) is independently H, D, C₁-C₁₀ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl,        heteroaryl, cycloalkyl, heterocycloalkyl, wherein said C₁-C₁₀        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —OC₁-C₆alkyl,        —O-cycloalkyl, aryl, heteroaryl, cycloalkyl, or        heterocycloalkyl, is optionally substituted;    -   or R^(c) and R^(d), together with the N atom to which they are        both attached, form an optionally substituted monocyclic or        multi cyclic -4-10 membered heterocycloalkyl group.

-   Aspect 3. The compound according to either aspect 1 or aspect 2, or    a pharmaceutically acceptable salt or solvate thereof, wherein said    compound has the Formula IA:

-   -   wherein W¹ is —CH₂— and W³ is —O—, or W¹ is —O— and W³ is —CH₂—,        or W¹ is —CH₂— and W³ is —S—, or W¹ is —S— and W³ is —CH₂—, or        W¹ is —CH₂— and W³ is —NR^(2B)—, or W¹ is —NR^(2B)— and W³ is        —CH₂—, or W¹ is —CH₂— and W³ is —CH₂—.

-   Aspect 4. The compound according to aspect 3, or a pharmaceutically    acceptable salt or solvate thereof, wherein said compound has the    Formula IA-1:

-   Aspect 5. The compound according to aspect 4, wherein W¹ is —CH₂— or    —O—.-   Aspect 6. A compound according to aspect 3, or a pharmaceutically    acceptable salt or solvate thereof, wherein said compound has the    Formula IA-2:

-   Aspect 7. The compound according to aspect 6, wherein W³ is —CH₂— or    —O—.-   Aspect 8. The compound according to aspect 3, or a pharmaceutically    acceptable salt or solvate thereof, wherein said compound has the    Formula IA-3:

wherein W¹ is —CH₂— and W³ is O, or W¹ is —O— and W³ is —CH₂—, or W¹ is—CH₂— and W³ is —CH₂—.

-   Aspect 9. The compound according to any one of aspects 1-8, wherein    L¹ is optionally substituted C₁alkylene.-   Aspect 10. The compound according to aspect 9, wherein L¹ is —CH₂—.-   Aspect 11. The compound according to any one of aspects 1-10,    wherein L² is optionally substituted cycloalkylene or optionally    substituted heterocycloalkylene.-   Aspect 12. The compound according to aspect 11, wherein L¹ is —CH₂—;    and L² is optionally substituted cyclobutylene or optionally    substituted pyrrolidine.-   Aspect 13. The compound according to any one of aspects 1-12,    wherein said compound is a compound of Formula IA-4:

-   -   or a pharmaceutically acceptable salt or solvate thereof;        wherein        -   W¹ is —CH₂— and W³ is O, or W¹ is —O— and W³ is —CH₂—, or W¹            is —CH₂— and W³ is —CH₂—;    -   L³ is absent, or is —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —S(O)—,        —S(O)₂—, —C(═O)—, —C(═O)O—, —C(═O)NR^(6A)—, —NR^(6A)C(O)O—,        —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or        —NR^(6A)S(O)₂—;    -   L⁴ is absent, or —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is        absent, —CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—,        —NR⁶—, —OC(═O)—, —C(═O)O—, —NR^(6A)C(O), —C(═O)NR^(6A)—,        —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—,        —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or        —NR^(6A)S(O)₂—;    -   L⁵ is absent, or is a 6- to 10-membered arylene, 5- to        10-membered heteroarylene, a 3- to 12-membered cycloalkenylene,        a 3- to 12-membered cycloalkenylene, a 3- to 7-membered        monocyclic cycloalkylene, a 6- to 12 bicyclic cycloalkylene, a        3- to 7-membered monocyclic heterocycloalkylene, or 6- to        12-membered bicyclic heterocycloalkylene group, wherein the 6-        to 10-membered arylene, 5- to 10-membered heteroarylene, a 3- to        12-membered cycloalkenylene, a 3- to 12-membered        cycloalkenylene, a 3- to 7-membered monocyclic cycloalkylene, a        6- to 12 bicyclic cycloalkylene, a 3- to 7-membered monocyclic        heterocycloalkylene, or 6- to 12-membered bicyclic        heterocycloalkylene group is optionally substituted; and    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—, —O(CR⁷R⁸)_(t)—,        —NR⁹(CR⁷R⁸)_(t)—, —S(CR⁷R⁸)_(t)—, —S(O)(CR⁷R⁸)_(t)—,        —S(O)₂(CR⁷R⁸)_(t)—, —NR^(9A)C(O)(CR⁷R⁸)_(t)—,        —C(O)NR^(9A)(CR⁷R⁸)_(t)—, —R^(9A)C(O)O(CR⁷R⁸)_(t)—,        —NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—, —NR^(9A)S(O)(CR⁷R⁸)_(t)—,        —NR^(9A)S(O)₂(CR⁷R⁸)_(t)—; —CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—,        —C(═O)(CR⁷R⁸)_(t)—; —C(═O)(CR⁷R⁸)_(t)—O—, or        —C(═O)(CR⁷R⁸)_(t)—NR⁶—.

-   Aspect 14. The compound according to any one of aspects 1-13, or a    pharmaceutically acceptable salt or solvate thereof; wherein    -   L³ absent;    -   L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is absent,        —CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—,        —OC(═O)—, —C(═O)O—, —NR^(6A)C(O), —C(═O)NR^(6A)—,        —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—,        —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or        —NR^(6A)S(O)₂—;    -   L⁵ is absent; and    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—, —O(CR⁷R⁸)_(t)—,        —NR⁹(CR⁷R⁸)_(t)—, —S(CR⁷R⁸)_(t)—, —S(O)(CR⁷R⁸)_(t)—,        —S(O)₂(CR⁷R⁸)_(t)—, —NR^(9A)C(O)(CR⁷R⁸)_(t)—,        —C(O)NR^(9A)(CR⁷R⁸)_(t)—, —R^(9A)C(O)O(CR⁷R⁸)_(t)—,        —NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—, —NR^(9A)S(O)(CR⁷R⁸)_(t)—,        —NR^(9A)S(O)₂(CR⁷R⁸)_(t)—; —CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—,        —C(═O)(CR⁷R⁸)_(t)—; —C(═O)(CR⁷R⁸)_(t)—O—, or        —C(═O)(CR⁷R⁸)_(t)—NR⁶—.

-   Aspect 15. The compound according to any one of aspects 1-14,    wherein    -   L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is        —CR^(4A)═CR^(4B)—; and    -   L⁶ is absent, —O(CR⁷R⁸)_(t)—, or —NR⁹(CR⁷R⁸)_(t)—.

-   Aspect 16. The compound according to any one of aspects 1-15,    wherein    -   p=1;    -   q=1-4; and    -   t=1.

-   Aspect 17. The compound according to any one of aspects 1-13, or a    pharmaceutically acceptable salt or solvate thereof; wherein    -   L³ absent;    -   L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is absent,        —CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—,        —OC(═O)—, —C(═O)O—, —NR^(6A)C(O), —C(═O)NR^(6A)—,        —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—,        —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or        —NR^(6A)S(═O)₂—;    -   L⁵ is a 6- to 10-membered arylene, 5- to 10-membered        heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to        12-membered cycloalkenylene, a 3- to 7-membered monocyclic        cycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to        7-membered monocyclic heterocycloalkylene, or 6- to 12-membered        bicyclic heterocycloalkylene group, wherein the 6- to        10-membered arylene, 5- to 10-membered heteroaryl ene, a 3- to        12-membered cycloalkenylene, a 3- to 12-membered        cycloalkenylene, a 3- to 7-membered monocyclic cycloalkylene, a        6- to 12 bicyclic cycloalkylene, a 3- to 7-membered monocyclic        heterocycloalkylene, or 6- to 12-membered bicyclic        heterocycloalkylene group is optionally substituted; and    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—.

-   Aspect 18. The compound according to any one of aspects 1-13 or 17,    wherein    -   L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is        —CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —OC(═O)—,        —C(═O)O—, —OC(═O)N(R^(6A))—, or —NR^(6A)C(O)O—;    -   L⁵ is a 6- to 10-membered arylene, 5- to 10-membered heteroaryl        ene, a 3- to 7-membered monocyclic cycloalkylene, a 3- to        7-membered monocyclic heterocycloalkylene, wherein the 6- to        10-membered arylene, 5- to 10-membered heteroarylene, a 3- to        7-membered monocyclic cycloalkylene, a 3- to 7-membered        monocyclic heterocycloalkylene is optionally substituted; and    -   L⁶ is absent, or is —(CR⁷R⁸)_(s)—.

-   Aspect 19. The compound according to any one of aspects 1 to 14, or    a pharmaceutically acceptable salt or solvate thereof; wherein L⁴ is    —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)— wherein p=1; q=1-3, Q¹ is absent, or    —CR^(4A)═CR^(4B)—; L⁶ is (CR⁷R⁸)_(s) wherein s=1-2, —O(CR⁷R⁸)_(t)—,    —NR⁹(CR⁷R⁸)_(t)—, —S(CR⁷R⁸)_(t)—, —S(O)(CR⁷R⁸)_(t)—, or    —S(O)₂(CR⁷R⁸)_(t)—, wherein t=1.

-   Aspect 20. The compound according to any one of aspects 1-14 or 19,    or a pharmaceutically acceptable salt or solvate thereof, wherein    said compound is a compound of Formula IA-8:

-   -   wherein X is O, NR⁹, CR⁷R⁸, S, S(O), SO₂;    -   R is halo or C₁-C₆alkyl;    -   represents a carbon-carbon single bond in which each carbon atom        in the bond is substituted with R⁴ and R⁵, an (E)-carbon-carbon        double bond, or a (Z)-carbon-carbon double bond;    -   R^(a*) is R^(a) wherein R^(a) is H, —C(O)R^(b), —C(O)OR^(c),        —C(O)NR^(c)R^(d), P(OR^(c))₂, P(O)R^(c)R^(b), P(O)OR^(c)OR^(b),        S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), S(O)₂NR^(c)R^(d),        B(OR^(c))(OR^(b)), SiR^(b)3, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl,        wherein said C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, aryl,        cycloalkyl, heteroaryl, or heterocycloalkyl is optionally        substituted;    -   R^(c)* is R^(c) wherein R^(c) is H, D, —C₁-C₁₀ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl, wherein said C₁-C₁₀ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, or        heterocycloalkenyl are each optionally substituted.

-   Aspect 21. The compound according to aspect 20, wherein    represents a carbon-carbon single bond in which each carbon atom in    the bond is substituted with R⁴ and R⁵.

-   Aspect 22. The compound according to aspect 20, wherein    represents a carbon-carbon double bond substituted with R^(4A) and    R^(4B).

-   Aspect 23. The compound according to aspect 22, wherein    represents a (E)-carbon-carbon double bond substituted with R^(4A)    and R^(4B).

-   Aspect 24. The compound according to any one of aspects 20-23,    wherein X is —O—, —NR⁹—, or —CR⁷R⁸—.

-   Aspect 25. The compound according to any one of aspects 20-24,    wherein R^(a)* is R^(a) wherein R^(a) is H, —C(O)R^(b), —C(O)OR^(c),    —C(O)NR^(c)R^(d), —S(O)₂R^(b), or optionally substituted C₁-C₆alkyl;    and R^(c)* is R^(c) wherein R^(c) is H or optionally substituted    C₁-C₁₀alkyl.

-   Aspect 26. The compound according to any one of aspects 20-25,    wherein R is —Cl.

-   Aspect 27. The compound according to any one of aspects 20-26,    wherein each R⁴ and R⁵ is independently H or C₁-C₆alkyl.

-   Aspect 28. The compound according to any one of aspects 1-14 or 19,    or a pharmaceutically acceptable salt or solvate thereof, wherein    said compound is a compound of Formula IA-5:

-   -   wherein X is —O—, —NR⁹—, —CR⁷R⁸—, —S—, —S(O)—, —SO₂—; R is halo        or C₁-C₆alkyl;    -   represents a carbon-carbon single bond in which each carbon atom        in the bond is substituted with R⁴ and R⁵, an (E)-carbon-carbon        double bond substituted with R^(4A) and R^(4B), or a        (Z)-carbon-carbon double bond substituted with R^(4A) and        R^(4B); and R^(a*) is R^(a) wherein R^(a) is H, —C(O)R^(b),        —C(O)OR^(c), —C(O)NR^(c)R^(d), P(OR^(c))₂, P(O)R^(c)R^(b),        P(O)OR^(c)OR^(b), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),        S(O)₂NR^(c)R^(d), B(OR^(c))(OR^(b)), SiR^(b) ₃, C₁-C₁₀alkyl,        C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, or        heterocycloalkyl, wherein said C₁-C₁₀ alkyl, C₂-C₁₀alkenyl,        C₂-C₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, or        heterocycloalkyl is optionally substituted.

-   Aspect 29. The compound according to aspect 28, wherein    represents a carbon-carbon single bond in which each carbon atom in    the bond is substituted with R⁴ and R⁵.

-   Aspect 30. The compound according to aspect 28, wherein    represents a carbon-carbon double bond substituted with R^(4A) and    R^(4B).

-   Aspect 31. The compound according to any one of aspects 28-30wherein    X is —O—, —NR⁹—, or —CR⁷R⁸—.

-   Aspect 32. The compound according to any one of aspects 28-31,    wherein R^(a*) is R^(a) wherein R^(a) is H, —C(O)R^(b),    —C(O)NR^(c)R^(d), optionally substituted C₁-C₁₀alkyl, optionally    substituted C₂-C₁₀alkenyl, optionally substituted C₂-C₁₀ alkynyl,    optionally substituted aryl, optionally substituted cycloalkyl,    optionally substituted heteroaryl, or optionally substituted    heterocycloalkyl.

-   Aspect 33. The compound according to aspect 30, having the structure    IA-6:

-   -   or a pharmaceutically acceptable salt or solvate thereof;        -   wherein X is —O—, —NR⁹—, or —CR⁷R⁸—; and        -   W¹ is —CH₂— and W³ is O, or W¹ is —O— and W³ is —CH₂—, or W¹            is —CH₂— and W³ is —CH₂—.

-   Aspect 34. The compound according to any one of aspects 28-33,    wherein each R⁴ or R⁵ is independently H, D, or C₁-C₆alkyl.

-   Aspect 35. The compound according to any one of aspects 20-34,    wherein X is —CR⁷R⁸—.

-   Aspect 36. The compound according to any one of aspects 20-34,    wherein X is —O—.

-   Aspect 37. The compound according to any one of aspects 20-34,    wherein X is —NR⁹—.

-   Aspect 38. The compound according to aspect 37, wherein X is —NR⁹—    wherein R⁹ is H; optionally substituted —C₁-C₆alkyl; optionally    substituted —C(O)OC₁-C₆alkyl; optionally substituted —SO₂C₁-C₆alkyl;    optionally substituted —C(O)C₁-C₆alkyl; optionally substituted    —C(O)NR^(c)R^(d); or wherein R⁹ together with either R⁷ or R⁸ form    an optionally substituted C₁-C₆alkylene group.

-   Aspect 39. The compound according to aspect 38, wherein X is —NR⁹—    wherein R⁹ is H; —C₁-C₆alkyl, optionally substituted with deuterium;    —C(O)OC₁-C₆alkyl; —SO₂C₁-C₆alkyl; —C(O)C₁-C₆alkyl; or wherein R⁹    together with either R⁷ or R⁸ form a C₁-C₆alkylene group.

-   Aspect 40. The compound according to aspect 39, wherein X is —NR⁹—    wherein R⁹ is H; —CH₃; —CH₂CH₃, —CH₂CH₂CH₃, —CD₃, —C(O)OCH₃;    —C(O)OC(CH₃)₃, —SO₂CH₃; or —C(O)CH₃.

-   Aspect 41. The compound according to anyone of aspects 20-40,    wherein each R⁷ and each R⁸ is independently H, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl, or    optionally substituted —C₁-C₆alkyl;    -   or R⁷ and R⁸ attached to the same carbon atom, together with        that carbon atom, form an optionally substituted cycloalkyl ring        or an optionally substituted heterocycloalkyl ring;    -   or R⁷ and R⁸ attached to adjacent carbon atoms, together with        those carbon atoms, form an optionally substituted cycloalkyl        ring or and optionally substituted heterocycloalkyl ring.

-   Aspect 42. The compound of aspect 41, wherein each R⁷ and each R⁸ is    independently H, optionally substituted 3-7 membered cycloalkyl, 4-7    membered heterocycloalkyl, or optionally substituted —C₁-C₆alkyl;    -   or wherein R⁷ and R⁸ attached to the same carbon atom, together        with that carbon atom, form an optionally substituted 3-7        membered cycloalkyl ring or an optionally substituted 4-7        membered heterocycloalkyl ring;    -   or R⁷ and R⁸ attached to adjacent carbon atoms, together with        those carbon atoms, form an optionally substituted 3-7 membered        cycloalkyl ring or an optionally substituted 4-7 membered        heterocycloalkyl ring.

-   Aspect 43. The compound of aspect 42, wherein R⁷ and R⁸ attached to    the same carbon atom, together with that carbon atom, form a 3-7    membered cycloalkyl ring or 4-7 membered heterocycloalkyl ring;    -   or R⁷ and R⁸ attached to adjacent carbon atoms, together with        the atoms to which they are attached, form a 3-7 membered        cycloalkyl ring or 4-7 membered heterocycloalkyl ring.

-   Aspect 44. The compound of aspect 42, wherein R⁷ or R⁸ are each    independently H, —CH₃, -cyclopropyl, —CH₂CH₃, or —CH(CH₃)₂.

-   Aspect 45. The compound of aspect 42, wherein R⁷ and R⁸ attached to    the same carbon atom, together with that carbon atom, form a    cyclopropyl ring, a cyclobutyl ring, or azetidinyl ring.

-   Aspect 46. The compound of aspect 41, wherein each R⁷ and each R⁸ is    independently H, or a —C₁-C₆alkyl group optionally substituted with    —OH; optionally substituted —OC₁-C₆alkyl; optionally substituted    —(CH₂CH₂O)_(o)C₁-C₆alkyl wherein o is 1-10; or —C(O)NR^(c1)R^(d1)    wherein R^(c1) and R^(d1) are independently H, optionally    substituted —C₁-C₆alkyl, optionally substituted cycloalkyl, or    optionally substituted heterocycloalkyl; or wherein or R^(c1) and    R^(d1), together with the N atom to which they are both attached,    form an optionally substituted monocyclic or multicyclic    heterocycloalkyl ring.

-   Aspect 47. The compound of aspect 46, wherein the —C₁-C₆alkyl group    is optionally substituted with —OH; —OC₁-C₆alkyl;    —(CH₂CH₂O)_(o)C₁-C₆alkyl wherein o is 1-10; or —C(O)NR^(c1)R^(d1)    wherein R^(c1) and R^(d1) are independently H, C₁-C₆alkyl, or 4-7    membered heterocycloalkyl; or wherein or R^(c1) and R^(d1), together    with the N atom to which they are both attached, form a monocyclic    or multicyclic 4-7 membered heterocycloalkyl ring optionally    substituted with halo; —OC₁-C₆alkyl; or —C₁-C₆alkyl optionally    substituted with —OH or —OC₁-C₆alkyl.

-   Aspect 48. The compound of any one of aspects 28-47, wherein R^(a*)    is R^(a) wherein R^(a) is H.

-   Aspect 49. The compound of any one of aspects 28-47, wherein R^(a*)    is R^(a) wherein R^(a) is —C(O)R^(b).

-   Aspect 50. The compound of any one of aspects 28-47, wherein R^(a*)    is R^(a) wherein R^(a) is —C(O)R^(b) wherein R^(b) is optionally    substituted —C₁-C₆alkyl.

-   Aspect 51. The compound of aspect 50, wherein R^(a*) is R^(a)    wherein R^(a) is —C(O)R^(b) wherein R^(b) is —C₁-C₆alkyl.

-   Aspect 52. The compound of aspect 51, wherein R^(a*) is R^(a)    wherein R^(a) is —C(O)R^(b) wherein R^(b) is —CH₃.

-   Aspect 53. The compound of any one of aspects 28-47, wherein R^(a*)    is R^(a) wherein R^(a) is —C(O)NR^(c)R^(d).

-   Aspect 54. The compound of any one of aspects 28-47, wherein R^(a*)    is R^(a) wherein R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d)    are independently H; optionally substituted —OC₁-C₆alkyl; optionally    substituted cycloalkyl; optionally substituted —C₁-C₆alkyl, or    optionally substituted heterocycloalkyl.

-   Aspect 55. The compound of aspect 54, wherein R^(a*) is R^(a)    wherein R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d) are    independently H; optionally substituted 3-7 membered cycloalkyl;    —OC₁-C₆alkyl; —C₁-C₆alkyl (optionally substituted with deuterium,    halo, optionally substituted cycloalkyl, optionally substituted    —OC₁-C₆alkyl, —NR^(c1)R^(d1) wherein R^(c1) and R^(d1) are    independently H or optionally substituted —C₁-C₆alkyl, optionally    substituted 4-7 membered heterocycloalkyl, or optionally substituted    5-6 membered heteroaryl); or optionally substituted 4-7 membered    heterocycloalkyl.

-   Aspect 56. The compound aspect 54, wherein R^(a*) is R^(a) wherein    R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d) are independently    H; 3-7 membered cycloalkyl; —C₁-C₆alkyl (optionally substituted with    deuterium, halo, —OC₁-C₆alkyl, cycloalkyl, —NR^(c1)R^(d1) wherein    R^(c1) and R^(d1) are independently H or —C₁-C₆alkyl, 4-7 membered    heterocycloalkyl (optionally substituted with halo, —C₁-C₆alkyl,    —OH, or —OC₁-C₆alkyl), or -5-6 membered heteroaryl), —OC₁-C₆alkyl;    or -4-7 membered heterocycloalkyl optionally substituted with    —C₁-C₆alkyl or —OH.

-   Aspect 57. The compound of any one of aspects 33-39, wherein R^(a*)    is R^(a) wherein R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d),    together with the nitrogen atom to which they are both attached,    form an optionally substituted monocyclic or multicyclic    heterocycloalkyl group.

-   Aspect 58. The compound of aspect 47, wherein R^(a*) is R^(a)    wherein R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d), together    with the nitrogen atom to which they are both attached, form a    monocyclic or multicyclic heterocycloalkyl group optionally    substituted with -halo, —OH, optionally substituted -4-7 membered    heterocycle, optionally substituted 5-6 membered heteroaryl,    optionally substituted —OC₁-C₆alkyl, optionally substituted    —C₁-C₆alkyl; or —NR^(c1)R^(d1) wherein R^(c1) and R^(d1) are    independently H or optionally substituted C₁-C₆alkyl,

-   Aspect 59. The compound of aspect 28-47, wherein R^(a*) is R^(a)    wherein R^(a) is —C(O)NR^(c)R^(d) wherein R^(c) and R^(d), together    with the nitrogen atom to which they are both attached, form a    monocyclic or multicyclic -4-10 membered heterocycloalkyl group    optionally substituted with -halo, —OH, -4-7 membered heterocycle,    5-6 membered heteroaryl, —OC₁-C₆alkyl, —C₁-C₆alkyl (optionally    substituted with —OH, —OC₁-C₆alkyl, or NR^(c1)R^(d1) wherein R^(c1)    and R^(d1) are independently H or C₁-C₆alkyl); or —NR^(c1)R^(d1)    wherein R^(c1) and R^(d1) are independently H or C₁-C₆alkyl.

-   Aspect 60. The compound according to any one of aspects 28-47,    wherein R^(a*) is R^(a) wherein R^(a) is optionally substituted    —C₁-C₆alkyl.

-   Aspect 61. The compound of aspect 60, wherein R^(a*) is R^(a)    wherein R^(a) is —C₁-C₁₀alkyl optionally substituted with    —C(O)NR^(c1)R^(d1), wherein R^(c1) and R^(d1) are independently H,    optionally substituted C₁-C₆alkyl, or optionally substituted    heterocyclyl; or wherein or R^(c1) and R^(d1), together with the N    atom to which they are both attached, form an optionally substituted    monocyclic or multicyclic -4-10 membered heterocycloalkyl group;    —NR^(c1)R^(d1) wherein R^(c1) and R^(d1) are independently H,    optionally substituted C₁-C₆alkyl, optionally substituted    cycloalkyl, or optionally substituted heterocycloalkyl; optionally    substituted heteroaryl; —C(O)OH; or optionally substituted    -heterocycloalkyl.

-   Aspect 62. The compound of aspect 61, wherein R^(a*) is R^(a)    wherein R^(a) is —C₁-C₁₀alkyl optionally substituted with    —C(O)NR^(c1)R^(d1), wherein R^(c1) and R^(d1) are independently H,    C₁-C₆alkyl (optionally substituted with —OC₁-C₆alkyl), or 4-7    membered heterocycloalkyl; or wherein or R^(c1) and R^(d1), together    with the N atom to which they are both attached, form a monocyclic    or multicyclic -4-10 membered heterocycloalkyl group (optionally    substituted with halo, —OC i-C₆alkyl, or —C₁-C₆alkyl (optionally    substituted with —OH or —OC₁-C₆alkyl)); —NR^(c1)R^(d1) wherein    R^(c1) and R^(d1) are independently H, or optionally substituted    C₁-C₆alkyl; —C₄-C₅heteroaryl; —C(O)OH; or -4-7 membered    heterocycloalkyl optionally substituted with halo, C₁-C₆alkyl, or    —OC₁-C₆alkyl.

-   Aspect 63. The compound according to any one of aspects 28-62,    wherein the compound has the structure (IA-7):

wherein W¹ is —CH₂— and W³ is —O—; or W¹ is —O— and W³ is —CH₂—; or W¹is —CH₂— and W³ is —CH₂₋.

-   Aspect 64. The compound according to aspect 63, wherein W¹ is —CH₂—    and W³ is —CH₂₋.-   Aspect 65. A compound, or a pharmaceutically acceptable salt or    solvate thereof, wherein said compound is:-   (3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-ethylene-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one;-   (3R,6R,7R,8E,12S,22S)-6′-chloro-7-methoxy-12-methyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one;-   (3R,6R,7R,8E,12R,22S)-6′-chloro-7-methoxy-11,12-dimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-13-one;-   (3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one;-   (3R,6R,7R,8E,22S)-6′-chloro-7-hydroxy-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one;-   (3R,6R,7R,8E,22S)-6′-chloro-7-methoxy-11,12,12-trimethyl-15,15-dioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-Chloro-12,12-ethylene-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-11-(trideuteriomethyl)spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    3-(dimethylamino)azetidine-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    (3R)-3-(dimethylamino)pyrrolidine-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    4-methyl-1,4-diazepane-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-11-ethyl-12,12-dimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-11-propyl-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    4-methoxypiperidine-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-[2-(dimethylamino)ethyl]-N-methyl-carbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    3-methoxyazetidine-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-1-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    3-ethoxyazetidine-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    (3R)-3-methoxypyrrolidine-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    (3R)-3-ethoxypyrrolidine-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]morpholine-4-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    4-(2-m ethoxy ethyl)-1,4-diazepane-1-carboxylate;-   [(3R,6R,7S,8E,22S)-7′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]    N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-[(3R)-tetrahydrofuran-3-yl]carbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-[(3S)-tetrahydrofuran-3-yl]carbamate;-   (3R,6R,7S,8E,22S)-6′-chloro-7-[2-(dimethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one;-   (3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-15,15-dioxo-7-(2-pyrrolidin-1-ylethoxy)spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-13-one;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    (3R)-3-methoxypyrrolidine-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methoxy-N-methyl-carbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-1,3-propylene-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1′-tetralin]-7-yl]    N-methyl-N[2-(dimethylamino)ethyl] carbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-11,12,12-trimethyl-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate;-   [(3R,6R,7S,8E,    22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N,N-bis(trideuteriomethyl)carbamate;-   2-[(3R,6R,7S,8E,22S)-6′-chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]oxy-N-tetrahydropyran-4-yl-acetamide;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methyl-N-(oxetan-3-yl)carbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methyl-N-tetrahydropyran-4-yl-carbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methyl-N-tetrahydropyran-4-yl-carbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-10,12,12-trimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-6′-chloro-7,12,12-trimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N,N-dimethylcarbamate;-   [(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]    N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate;-   [(3R,6R,7S,8E,22S)-7′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-7-yl]    N-methoxy-N-methyl-carbamate;-   [(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-[2-(dimethylamino)ethyl]-N-methyl-carbamate;-   [(3R,6R,7S,8E,22S)-6′-Chloro-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    (3R)-3-ethoxypyrrolidine-1-carboxylate;-   [(3R,6R,7S,8E,22S)-6′-Chloro-10,10-dideuterio-12,12-dimethyl-13,15,15-trioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N,N-dimethylcarbamate;-   (3R,6R,7S,8E,22S)-7′-chloro-7-[2-(dimethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one;-   (3R,6R,7S,8E,22S)-7′-chloro-7-[2-(diethylamino)ethoxy]-12,12-dimethyl-15,15-dioxo-spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one;-   (3R,6R,7S,8E,22S)-7′-chloro-12,12-dimethyl-15,15-dioxo-7-(2-pyrrolidin-1-ylethoxy)spiro[11,20-dioxa-15-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,4′-chromane]-13-one;-   [(3R,6R,7S,8E,22S)-6′-chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methyl-N-(oxetan-3-yl)carbamate; or-   [(3R,6R,7S,8E,22S)-6′-chloro-11-methyl-12,12-(1,3-propylene)-13,15,15-trioxo-spiro[20-oxa-15-thia-1,11,14-triazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16,18,24-tetraene-22,1′-tetralin]-7-yl]    N-methyl-N-[(3R)-tetrahydrofuran-3-yl]carbamate.-   Aspect 66. A pharmaceutical composition comprising a compound    according to any one of aspects 1 to 65 and a pharmaceutically    acceptable excipient.-   Aspect 67. A method of inhibiting an MCL-1 enzyme comprising    contacting the MCL-1 enzyme with an effective amount of a compound    of any one of aspects 1 to 65.-   Aspect 68. A method of treating a disease or disorder associated    with aberrant MCL-1 activity in a subject comprising administering    to the subject, a compound of any one of aspects 1 to 65.-   Aspect 69. The method of aspect 68, wherein the disease or disorder    associated with aberrant MCL-1 activity is colon cancer, breast    cancer, small-cell lung cancer, non-small-cell lung cancer, bladder    cancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia,    lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

What is claimed:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein Z isCH or N; Q is —O—, —S—, —S(O)—, or —S(O)₂—; the moiety -W¹-W²-W³ is—CR²R^(2A)—CR²R^(2A)—CR²R^(2A)—, —O—CR^(2B)R^(2C)—CR²R^(2A)—,—CR²R^(2A)—CR^(2B)R^(2C)—O—, —NR^(2B)—CR^(2B)R^(2C)—CR²R^(2A)—,—CR²R^(2A)—CR^(2B)R^(2C)—NR^(2B)—, —S—CR^(2B)R^(2C)—CR²R^(2A), or—CR²R^(2A)—CR^(2B)R^(2C)—S—; L¹ is absent or is optionally substituted—C₁-C₆alkylene-; L² is absent or is optionally substitutedcycloalkylene, optionally substituted heterocycloalkylene, optionallysubstituted arylene, or optionally substituted heteroarylene; L³ isabsent, or is —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —O—, —S—, —S(O)—, —S(O)₂—,—C(═O)—, —NR⁶—, —OC(═O)—, —C(═O)O—, —NR^(6A)C(O)—, —C(═O)NR^(6A)—,—OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—,—S(═O)₂NR^(6A)—, or —NR^(6A)S(O)₂—; L⁴ is absent, or is—(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is absent, —CR^(4A)═CR^(4B)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—, —C(═O)O—,—NR^(6A)C(O)—, —C(═O)NR^(6A)—, —NR^(6A)C(O)R^(6B)—, —OC(═O)N(R^(6A))—,—NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or—NR^(6A)S(O)₂—; or is —(CR⁴R⁵)_(p)—(CR^(4A)═CR^(4B))—(CR⁴R⁵)_(q)—O—; L⁵is absent, or is —C₁-C₆ alkylene-, —C₂-C₆ alkenylene-, —C₂-C₆alkynylene-, -arylene-, -heteroarylene-, -cycloalkenylene-,-cycloalkylene-, -heterocycloalkylene-, wherein said C₁-C₆ alkylene,C₂-C₆ alkenylene, C₂-C₆ alkynylene, arylene, heteroarylene,cycloalkenylene, cycloalkylene, or heterocycloalkylene groups areoptionally substituted; L⁶ is absent, or is —(CR⁷R⁸)_(s)—,—(CR⁷R⁸)_(s)O(CR⁷R⁸)_(t)—, —(CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t)—,—(CR⁷R⁸)_(s)S(CR⁷R⁸)_(t)—, —(CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t)—,—(CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t)—, —(CR⁷R⁸)_(s)NR^(9A)C(O)(CR⁷R⁸)_(t)—,—(CR⁷R⁸)_(s)OC(O)NR^(9A)(CR⁷R⁸)_(t)—,—(CR⁷R⁸)_(s)NR^(9A)C(O)O(CR⁷R⁸)_(t)—,—(CR⁷R⁸)_(s)NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—,—(CR⁷R⁸)_(s)NR^(9A)S(O)(CR⁷R⁸)_(t)—,—(CR⁷R⁸)_(s)NR^(9A)S(O)₂(CR⁷R⁸)_(t)—;—(CR⁷R⁸)_(s)—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—,—(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—; —(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—O—, or—(CR⁷R⁸)_(s)C(═O)(CR⁷R⁸)_(t)—NR⁶—; each n is independently 0-3; each mis independently 0-2; each p is independently 0-4; each q isindependently 0-4; each s is independently 0-3; each t is independently0-4; each R is independently -D, -halo, —CN, —NO₂, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₁-C₆alkoxy, -cycloalkyl, —OR^(a), —SR^(a), —C(O)R^(b),—C(O)OR^(a), —NR^(c)R^(d), —C(O)NR^(c)R^(d), or —S(O)₂R^(a); whereinsaid —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₁-C₆alkoxy, or -cycloalkyl isoptionally substituted; each R¹ is independently -D, -halo, —CN, —NO₂,—C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, —OR^(a), —SR^(a),—NR^(c)R^(d), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(a), —C(O)NR^(c)R^(d),—S(O)₂R^(a); -aryl, -heteroaryl, -cycloalkyl, or -heterocycloalkyl,wherein said —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, -cycloalkyl,-heterocycloalkyl, -aryl, or -heteroaryl is optionally substituted; eachR², R^(2A), or R^(2a) is independently H, D, halo, OR^(a), optionallysubstituted C₁-C₆alkyl, or R² and R^(2A) that are attached to the samecarbon atom may, together with the carbon atom to which they are bothattached, form an optionally substituted cycloalkyl ring; each R^(2B)and R^(2C) is independently H, D, optionally substituted C₁-C₆alkyl, orR^(2B) and R^(2C) may, together with the carbon atom to which they areboth attached, form an optionally substituted cycloalkyl ring; R³ is H,D, —C₁-C₆alkyl, —C₃-C₆alkenyl, —C₃-C₆alkynyl, cycloalkyl,heterocycloalkyl, C(O)R^(b), C(O)OR^(a), or C(O)NR^(c)R^(d); whereinsaid C₁-C₆alkyl, —C₃-C₆alkenyl, —C₃-C₆alkynyl, cycloalkyl, orheterocycloalkyl is optionally substituted; or R³ is —C₁-C₆alkylsubstituted at the C₁ carbon atom with —OR^(3A) wherein R^(3A) isC₁-C₆alkyl, —PO₃H, —C(O)OR^(2C), or —C(O)NR^(3A)R^(3B) wherein R^(3A)and R^(3B) are each independently H, D, optionally substitutedC₁-C₆alkyl; each R⁴ or R⁷ is independently H, D, halo, —OH, —CN, —NO₂,—C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —OR^(a), —SR^(a),—NR^(c)R^(d), —NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(a), —C(O)OR^(a),—C(O)NR^(c)R^(d), —S(O)R^(b), or —S(O)₂R^(b), wherein said C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkenyl, or heterocycloalkyl is optionallysubstituted; each R^(4A) or R^(4B) is independently H, D, -Me, —CF₃ or—F; each R⁵ or R⁸ is independently H, D, fluoro, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —C(O)R^(b), —C(O)OR^(a), —C(O)NR^(c)R^(d),aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, wherein said C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl is optionally substituted; or R⁴and R⁵ together with the C atom to which they are attached form acycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring,each optionally substituted; or an R⁴ and an R⁵ attached to adjacentcarbon atoms, together with the C atoms to which they are attached, forma cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenylring, each optionally substituted; or R⁷ and R⁸ together with the C atomto which they are both attached form a cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl ring, each optionallysubstituted, each optionally substituted; or an R⁷ and an R⁸ attached toadjacent carbon atoms, together with the C atoms to which they areattached, form a cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl ring, each optionally substituted; each R⁶ or R⁹ isindependently H, D, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—OC₁-C₆alkyl, —C(O)R^(b), —C(O)OR^(a), —C(O)NR^(c)R^(d), —S(O)R^(b) or—S(O)₂R^(b), aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group, wherein said C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —OC₁-C₆alkyl, aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring,is optionally substituted; or R⁹ together with either an R⁷ or an R⁸forms an optionally substituted heterocyclic alkylene; each R^(6A),R^(6B), R^(9A), or R^(9B) is independently H, D, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl, wherein said C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl is optionally substituted; orR^(6A) and R^(6B) together with the N atoms to which they are attachedform an optionally substituted heterocycloalkyl or heterocycloalkenylring; or R^(9A) and R^(9B) together with the N atoms to which they areattached form an optionally substituted heterocycloalkyl orheterocycloalkenyl ring; each R^(a) is independently H, D, —C(O)R^(b),—C(O)OR^(c), —C(O)NR^(c)R^(d), —P(OR^(c))₂, —P(O)R^(c)R^(b),—P(O)OR^(c)OR^(b), —S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b),—S(O)₂NR^(c)R^(d), —B(OR^(c))(OR^(b)), SiR^(b) ₃, —C₁-C₁₀alkyl, —C₂-C₁₀alkenyl, —C₂-C₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,heterocycloalkyl, or heterocycloalkenyl wherein said C₁—C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl,heteroaryl, heterocycloalkyl, or heterocycloalkenyl is optionallysubstituted; each R^(b), is independently H, D, —C₁-C₆ alkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,heterocycloalkyl, or heterocycloalkenyl wherein said —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₂-C₆ alkynyl, aryl, cycloalkyl, cycloalkeneyl,heteroaryl, heterocycloalkyl, or heterocycloalkenyl is optionallysubstituted; each R^(c) or R^(d) is independently H, D, —C₁-C₁₀ alkyl,—C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl,heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, wherein said C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl are eachoptionally substituted; or R^(c) and R^(d), together with the N atom towhich they are both attached, form an optionally substituted monocyclicor multicyclic heterocycloalkyl, or optionally substituted monocyclic ormulticyclic heterocycloalkenyl group.
 2. The compound according to claim1, or a pharmaceutically acceptable salt or solvate thereof, whereinsaid compound has the Formula IA-3:

wherein W¹ is —CH₂— and W³ is O, or W¹ is —O— and W³ is —CH₂—, or W¹ is—CH₂— and W³ is —CH₂—
 3. The compound according to claim 1, wherein L²is optionally substituted cycloalkylene or optionally substitutedheterocycloalkylene.
 4. The compound according to claim 1, wherein saidcompound is a compound of Formula IA-4:

or a pharmaceutically acceptable salt or solvate thereof; wherein W¹ is—CH₂— and W³ is O, or W¹ is —O— and W³ is —CH₂—, or W¹ is —CH₂— and W³is —CH₂—; L³ is absent, or is —(CR⁴R⁵)_(p)—, —(CR⁴R⁵)_(p)O—, —S(O)—,—S(O)₂—, —C(═O)—, —C(═O)O—, —C(═O)NR^(6A)—, —NR^(6A)C(O)O—,—S(═O)NR^(6A)—, —NR^(6A)S(O)—, —S(═O)₂NR^(6A)—, or —NR^(6A)S(O)₂—; L⁴ isabsent, or —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is absent,—CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—,—C(═O)O—, —NR^(6A)C(O), —C(═O)NR^(6A)—, —NR^(6A)C(O)R^(6B)—,—OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—,—S(═O)₂NR^(6A)—, or —NR^(6A)S(O)₂—; L⁵ is absent, or is a 6- to10-membered arylene, 5- to 10-membered heteroarylene, a 3- to12-membered cycloalkenylene, a 3- to 12-membered cycloalkenylene, a 3-to 7-membered monocyclic cycloalkylene, a 6- to 12 bicycliccycloalkylene, a 3- to 7-membered monocyclic heterocycloalkylene, or 6-to 12-membered bicyclic heterocycloalkylene group, wherein the 6- to10-membered arylene, 5- to 10-membered heteroarylene, a 3- to12-membered cycloalkenylene, a 3- to 12-membered cycloalkenylene, a 3-to 7-membered monocyclic cycloalkylene, a 6- to 12 bicycliccycloalkylene, a 3- to 7-membered monocyclic heterocycloalkylene, or 6-to 12-membered bicyclic heterocycloalkylene group is optionallysubstituted; and L⁶ is absent, or is —(CR⁷R⁸)_(s)—, —O(CR⁷R⁸)_(t)—,—NR⁹(CR⁷R⁸)_(t)—, —S(CR⁷R⁸)_(t)—, —S(O)(CR⁷R⁸)_(t)—, —S(O)₂(CR⁷R⁸)_(t)—,—NR^(9A)C(O)(CR⁷R⁸)_(t)—, —C(O)NR^(9A)(CR⁷R⁸)_(t)—,—R^(9A)C(O)O(CR⁷R⁸)_(t)—, —NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—,—NR^(9A)S(O)(CR⁷R⁸)_(t)—, —NR^(9A)S(O)₂(CR⁷R⁸)_(t)—;—CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—, —C(═O)(CR⁷R⁸)_(t)—; —C(═O)(CR⁷R⁸)_(t)—O—,or —C(═O)(CR⁷R⁸)_(t)—NR⁶—.
 5. The compound according to claim 1, or apharmaceutically acceptable salt or solvate thereof; wherein L³ absent;L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is absent,—CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—, —OC(═O)—,—C(═O)O—, —NR^(6A)C(O), —C(═O)NR^(6A)—, —NR^(6A)C(O)R^(6B)—,—OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—,—S(═O)₂NR^(6A)—, or —NR^(6A)S(O)₂—; L⁵ is absent; and L⁶ is absent, oris —(CR⁷R⁸)_(s)—, —O(CR⁷R⁸)_(t)—, —NR⁹(CR⁷R⁸)_(t)—, —S(CR⁷R⁸)_(t)—,—S(O)(CR⁷R⁸)_(t)—, —S(O)₂(CR⁷R⁸)_(t)—, —NR^(9A)C(O)(CR⁷R⁸)_(t)—,—C(O)NR^(9A)(CR⁷R⁸)_(t)—, —R^(9A)C(O)O(CR⁷R⁸)_(t)—,—NR^(9A)C(O)NR^(9B)(CR⁷R⁸)_(t)—, —NR^(9A)S(O)(CR⁷R⁸)_(t)—,—NR^(9A)S(O)₂(CR⁷R⁸)_(t)—; —CR^(4A)═CR^(4B)—(CR⁷R⁸)_(t)—,—C(═O)(CR⁷R⁸)_(t)—; —C(═O)(CR⁷R⁸)_(t)—O—, or —C(═O)(CR⁷R⁸)_(t)—NR⁶—. 6.The compound according to claim 1, wherein L⁴ is—(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —CR^(4A)═CR^(4B)—; and L⁶ isabsent, —O(CR⁷R⁸)_(t)—, or —NR⁹(CR⁷R⁸)_(t)—.
 7. The compound accordingto claim 1, wherein p=1; q=1-4; and t=1.
 8. The compound according toclaim 1, or a pharmaceutically acceptable salt or solvate thereof;wherein L³ absent; L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ isabsent, —CR^(4A)═CR^(4B)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —NR⁶—,—OC(═O)—, —C(═O)O—, —NR^(6A)C(O), —C(═O)NR^(6A)—, —NR^(6A)C(O)R^(6B)—,—OC(═O)N(R^(6A))—, —NR^(6A)C(O)O—, —S(═O)NR^(6A)—, —NR^(6A)S(O)—,—S(═O)₂NR^(6A)—, or —NR^(6A)S(═O)₂—; L⁵ is a 6- to 10-membered arylene,5- to 10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a3- to 12-membered cycloalkenylene, a 3- to 7-membered monocycliccycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-memberedmonocyclic heterocycloalkylene, or 6- to 12-membered bicyclicheterocycloalkylene group, wherein the 6- to 10-membered arylene, 5- to10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to12-membered cycloalkenylene, a 3- to 7-membered monocycliccycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-memberedmonocyclic heterocycloalkylene, or 6- to 12-membered bicyclicheterocycloalkylene group is optionally substituted; and L⁶ is absent,or is —(CR⁷R⁸)_(s)—.
 9. The compound according to claim 1, wherein L⁴ is—(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)—, wherein Q¹ is —CR^(4A)═CR^(4B)—, —O—, —S—,—S(O)—, —S(O)₂—, —C(═O)—, —OC(═O)—, —C(═O)O—, —OC(═O)N(R^(6A))—, or—NR^(6A)C(O)O—; L⁵ is a 6- to 10-membered arylene, 5- to 10-memberedheteroarylene, a 3- to 7-membered monocyclic cycloalkylene, a 3- to7-membered monocyclic heterocycloalkylene, wherein the 6- to 10-memberedarylene, 5- to 10-membered heteroaryl ene, a 3- to 7-membered monocycliccycloalkylene, a 3- to 7-membered monocyclic heterocycloalkylene isoptionally substituted; and L⁶ is absent, or is —(CR⁷R⁸)_(s)—.
 10. Thecompound according to claim 1, or a pharmaceutically acceptable salt orsolvate thereof; wherein L⁴ is —(CR⁴R⁵)_(p)Q¹(CR⁴R⁵)_(q)— wherein p=1;q=1-3, Q¹ is absent, or —CR^(4A)═CR^(4B)—; L⁶ is (CR⁷R⁸)_(s) whereins=1-2, —O(CR⁷R⁸)_(t)—, —NR⁹(CR⁷R⁸)_(t)—, —S(CR⁷R⁸)_(t)—,—S(O)(CR⁷R⁸)_(t)—, or —S(O)₂(CR⁷R⁸)_(t)—, wherein t=1.
 11. The compoundaccording to claim 1, or a pharmaceutically acceptable salt or solvatethereof, wherein said compound is a compound of Formula IA-8:

wherein X is O, NR⁹, CR⁷R⁸, S, S(O), SO₂; R is halo or C₁-C₆alkyl;

represents a carbon-carbon single bond in which each carbon atom in thebond is substituted with R⁴ and R⁵, an (E)-carbon-carbon double bond, ora (Z)-carbon-carbon double bond; R^(a*) is R^(a) wherein R^(a) is H,—C(O)R^(b), —C(O)OR^(c), —C(O)NR^(c)R^(d), P(OR^(c))₂, P(O)R^(c)R^(b),P(O)OR^(c)OR^(b), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),S(O)₂NR^(c)R^(d), B(OR^(c))(OR^(b)), SiR^(b) ₃, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, wherein said C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionallysubstituted; R^(c)* is R^(c) wherein R^(c) is H, D, —C₁-C₁₀ alkyl,—C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl,heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, wherein said C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl are eachoptionally substituted.
 12. The compound according to claim 11, wherein

represents a carbon-carbon single bond in which each carbon atom in thebond is substituted with R⁴ and R⁵.
 13. The compound according to claim11, wherein

represents a carbon-carbon double bond substituted with R^(4A) andR^(4B).
 14. The compound according to claim 13, wherein

represents a (E)-carbon-carbon double bond substituted with R^(4A) andR^(4B).
 15. The compound according to claim 11, wherein X is —O—, —NR⁹—,or —CR⁷R⁸—.
 16. The compound according to claim 11, wherein R^(a*) isR^(a) wherein R^(a) is H, —C(O)R^(b), —C(O)OR^(c), —C(O)NR^(c)R^(d),—S(O)₂R^(b), or optionally substituted C₁-C₆alkyl; and R^(c)* is R^(c)wherein R^(c) is H or optionally substituted C₁-C₁₀alkyl.
 17. Thecompound according to claim 11, wherein R is —Cl.
 18. The compoundaccording to claim 11, wherein each R⁴ and R⁵ is independently H orC₁-C₆alkyl.
 19. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable excipient.
 20. Amethod of inhibiting an MCL-1 enzyme comprising contacting the MCL-1enzyme with an effective amount of a compound of claim
 1. 21. A methodof treating a disease or disorder associated with aberrant MCL-1activity in a subject comprising administering to the subject, acompound of claim
 1. 22. The method of claim 21, wherein the disease ordisorder associated with aberrant MCL-1 activity is colon cancer, breastcancer, small-cell lung cancer, non-small-cell lung cancer, bladdercancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia,lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.